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Review ArticleReview Article

More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder

M. J. Moerke, L. R. McMahon and J. L. Wilkerson
Michael A. Nader, ASSOCIATE EDITOR
Pharmacological Reviews April 2020, 72 (2) 527-557; DOI: https://doi.org/10.1124/pr.119.018028
M. J. Moerke
Division of Preclinical Pharmacology, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (M.J.M.) and Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida (L.R.M., J.L.W.)
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  • For correspondence: megan.moerke@nih.gov
L. R. McMahon
Division of Preclinical Pharmacology, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (M.J.M.) and Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida (L.R.M., J.L.W.)
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J. L. Wilkerson
Division of Preclinical Pharmacology, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (M.J.M.) and Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida (L.R.M., J.L.W.)
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Michael A. Nader
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Abstract

Tobacco use is a persistent public health issue. It kills up to half its users and is the cause of nearly 90% of all lung cancers. The main psychoactive component of tobacco is nicotine, primarily responsible for its abuse-related effects. Accordingly, most pharmacotherapies for smoking cessation target nicotinic acetylcholine receptors (nAChRs), nicotine’s major site of action in the brain. The goal of the current review is twofold: first, to provide a brief overview of the most commonly used behavioral procedures for evaluating smoking cessation pharmacotherapies and an introduction to pharmacokinetic and pharmacodynamic properties of nicotine important for consideration in the development of new pharmacotherapies; and second, to discuss current and potential future pharmacological interventions aimed at decreasing tobacco use. Attention will focus on the potential for allosteric modulators of nAChRs to offer an improvement over currently approved pharmacotherapies. Additionally, given increasing public concern for the potential health consequences of using electronic nicotine delivery systems, which allow users to inhale aerosolized solutions as an alternative to smoking tobacco, an effort will be made throughout this review to address the implications of this relatively new form of nicotine delivery, specifically as it relates to smoking cessation.

Significance Statement Despite decades of research that have vastly improved our understanding of nicotine and its effects on the body, only a handful of pharmacotherapies have been successfully developed for use in smoking cessation. Thus, investigation of alternative pharmacological strategies for treating tobacco use disorder remains active; allosteric modulators of nicotinic acetylcholine receptors represent one class of compounds currently under development for this purpose.

I. Introduction

The year 2014 marked the 50th anniversary of the first Surgeon General’s report on tobacco in 1964, which officially linked lung cancer to cigarette smoking (U.S. Department of Health, Education, and Welfare, 1964). In 1964, 42% of Americans were cigarette smokers (U.S. Department of Health and Human Services, 2014), including the Surgeon General himself. Fifty years later, it is estimated that the number of Americans smoking cigarettes has dropped to about 20% (U.S. Department of Health and Human Services, 2014). This decline has generally been reflected in other high-income nations worldwide; meanwhile, the tobacco industry has redirected its efforts, and the numbers of cigarette smokers are increasing in low-income countries (World Health Organization, 2018). The World Health Organization (WHO) adopted a Framework Convention on Tobacco Control in 2005 with the purpose of collecting better data from global populations on tobacco smoking behavior; this was followed by an initiative in 2011 to reduce worldwide prevalence of smoking by 30% from 2010 to 2025 (World Health Organization, 2013). The most recent projections fall considerably short of that goal (World Health Organization, 2018); however, the WHO continues to focus on implementing strategies, specifically in low- and middle-income countries, that have successfully reduced the prevalence of cigarette smoking in America. These include increasing public awareness of the health consequences of smoking tobacco, enforcing bans on advertising and promotion of tobacco products, imposing higher taxes on tobacco and tobacco-related products, and providing resources that enable smokers to quit using tobacco. Still, estimates of global health care costs from tobacco use are upwards of 1.4 trillion dollars a year and second-hand smoke alone causes 1.2 million deaths annually (GBD 2017 Risk Factor Collaborators, 2018). Unequivocally, tobacco use remains a worldwide public health issue.

Cigarette smoking is the largest single cause of preventable death in the world, killing more than eight million people every year, or one person every 6 seconds (World Health Organization, 2012). Since 1964, it is estimated that 20 million Americans have died from cigarette smoking–related causes (U.S. Department of Health and Human Services, 2014). This includes not only cigarette smokers but also approximately 2.5 million nonsmokers from causes related to secondhand smoke and at least 100,000 infants from pregnancy complications and Sudden Infant Death Syndrome linked to parental smoking. Despite an overall national decline in the prevalence of cigarette smoking, it remains responsible for 480,000 deaths each year in the United States, a rate of mortality 10 times as high as the number of opioid overdose deaths in 2017 (U.S. Department of Health and Human Services, 2014; Scholl et al., 2018). Specifically, one of every three cancer deaths is linked to smoking, including nearly 90% of all lung cancer deaths. Smoking causes not only cancer of the mouth, throat, larynx, lungs, esophagus, pancreas, kidney, bladder, stomach, cervix, blood, liver, and colon, but it also causes diabetes mellitus, rheumatoid arthritis, inflammation, and impaired immune function. Globally, it is the cause of 14% of deaths from noncommunicable diseases in adults and at least 5% of deaths from communicable diseases (World Health Organization, 2012). Despite the risks of tobacco smoking, each day, nearly 2000 children in the United States under the age of 18 smoke their first cigarette (Lipari et al., 2017). Fifteen percent of those children will go on to be daily cigarette users; half will likely die of cigarette smoking–related causes (Lipari et al., 2017).

The word “addiction” is universally understood but difficult to define. Clinically, cigarette smokers may be diagnosed in one of two ways, depending on the classification system used. The International Classification of Diseases, currently in its 10th edition, refers to the cluster of symptoms typically recognized as addiction as “dependence syndrome” and, specifically, “nicotine dependence.” The most recent update of the classification system developed by the American Psychiatric Association, the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, prefers the terminology “substance use disorder” and, more specifically, “tobacco use disorder.” For the sake of clarity and consistency, we will refer to substance use disorders or tobacco use disorder for the remainder of this review. Substance use disorders are characterized by compulsive use of a substance both to produce its subjective effects and to alleviate symptoms associated with its absence. Nicotine is the primary psychoactive component in tobacco, and although other chemicals that are either present in tobacco or added as adulterants also play a role, nicotine has been identified as the primary compound responsible for maintaining tobacco use in humans (Henningfield et al., 1985; Stolerman and Jarvis, 1995). Accordingly, most of the currently approved smoking-cessation therapeutics target nicotine’s primary mechanism of action, nicotinic acetylcholine receptors (nAChRs).

The focus of this review is on the development of medications for tobacco use disorder. We summarize preclinical assays typically used to evaluate medications as well as pharmacokinetic and pharmacodynamic considerations required for the interpretation of preclinical results as they are likely to translate to humans. We discuss current pharmacotherapies approved by the U.S. Food and Drug Administration (FDA), experimental and emerging pharmacotherapies that target nAChRs, and other mechanisms to promote smoking cessation. Additionally, this review provides an updated overview of the preclinical literature relevant to allosteric modulators of nAChRs as pharmacotherapies for tobacco use disorder (Mohamed et al., 2015). Novel pharmacotherapies targeting nAChRs are also under development for the treatment of pain (see Bagdas et al., 2018b) and for neurodegenerative and psychiatric conditions (see Bertrand and Terry, 2018), but they are outside the scope of the current review. Finally, the expansion of electronic nicotine delivery systems (ENDS) in the consumer market has dramatically increased the consumption of nicotine independently of tobacco products. The long-term consequences of this practice, commonly referred to as vaping, are currently unknown. Nonetheless, an effort will be made throughout this review to address the implications of this growing trend of nicotine delivery, specifically as it relates to smoking cessation.

II. Preclinical Methods for Evaluating Potential Pharmacotherapies

A. Self-Administration

Self-administration is a behavioral assay that has traditionally served as the cornerstone for examining the abuse liability of drugs and can be used to evaluate potential pharmacotherapies for substance use disorders. In this assay, animals are trained to make an operant response, typically either a lever press or a nose poke, to receive a drug infusion. Typically, drugs in self-administration procedures are delivered via an intravenous injection, and the nicotine literature is no exception (Goodwin et al., 2015); however, vapor chambers have recently been used to deliver nicotine in animal studies (George et al., 2010), although no published studies have used this for nicotine self-administration to date. Nonetheless, nicotine can serve as a positive reinforcer and is self-administered by rodents (Collins et al., 1984; Corrigall and Coen, 1989; Donny et al., 1995; Valentine et al., 1997; Picciotto et al., 1998), nonhuman primates (Goldberg et al., 1981; Sannerud et al., 1994), and humans (Henningfield and Goldberg, 1983; Henningfield et al., 1983).

Early nicotine self-administration studies were successful in demonstrating that nicotine could serve as a reinforcer, but they were insufficient to characterize nicotine as a drug of abuse because nicotine did not maintain rates of behavior comparable to drugs such as cocaine (Deneau and Inoki, 1967). Although it has now been shown repeatedly and definitively that under certain conditions nicotine maintains rates of behavior equivalent to cocaine, the experimental variables that impact this behavior have been a consistent topic of study. For example, pretraining with food or a drug like cocaine is often used to facilitate acquisition of nicotine self-administration (Griffiths et al., 1979; Goldberg et al., 1981; Yanagita et al., 1983; Slifer and Balster, 1985). Also, because nicotine self-administration in animals is typically done intravenously, it has been argued that nicotine infusion rate is an important factor in nicotine self-administration, with slower rates supporting more robust self-administration in rats (Sorge and Clarke, 2009). However, it has also been shown that slower infusion rates of nicotine decrease self-administration (Wakasa et al., 1995; Wing and Shoaib, 2013). Furthermore, length of self-administration session has also been manipulated, and rats show signs of withdrawal when nicotine is removed from extended access sessions of self-administration (O’Dell et al., 2007a); however, limited access sessions have been shown to produce similar levels of dependence when sessions are conducted 7 days a week (Paterson and Markou, 2004). Thus, the relative importance of some variables in nicotine self-administration is open to debate.

One experimental variable that clearly influences the reinforcing effectiveness of nicotine is the schedule of reinforcement. A second order schedule of reinforcement was the first to demonstrate intravenous self-administration of nicotine at high rates (Goldberg et al., 1981). Another commonly used schedule of reinforcement in self-administration is the progressive ratio schedule of reinforcement (Donny et al., 1999; Brunzell et al., 2010; Cohen et al., 2012; Le Foll et al., 2012; Weaver et al., 2012; Gamaleddin et al., 2013; Garcia et al., 2014); this is typically used to estimate the maximum reinforcing effectiveness of a drug. In progressive ratio experiments, the number of responses required for a single drug infusion increases by some amount with each successive infusion instead of remaining constant. This allows for determination of a “breakpoint,” the point at which the response demand is high enough that the animal will no longer work to receive drug infusions. Thus, a favorable outcome for a potential pharmacotherapy for smoking cessation in a progressive ratio experiment would be to decrease the breakpoint or, in other words, make the animal less willing to work to receive an infusion of nicotine.

Another variable that is uniquely important to the study of nicotine self-administration is pairing of the nicotine infusion with some other unconditioned stimuli. In fact, some groups have specifically sought to better understand this relationahip and developed other variations on self-administration of nicotine that integrate both Pavlovian and operant conditioning components to study its effectiveness as a reinforcer. For example, it has been shown in rats that when a nonrewarding conditioned stimulus is paired with nicotine (the unconditioned stimulus), the nonrewarding conditioned stimulus is reinforced (Bevins and Palmatier, 2004). Furthermore, pairing this conditioned stimulus with access to nicotine increases the amount of nicotine that is self-administered. Among other benefits, studies like these can serve to help in our understanding of how other effects of cigarettes, such as the subjective feeling of holding a cigarette or drawing cigarette smoke into the lungs, might be related to smoking cessation and relapse.

Importantly, in the abovementioned self-administration procedures, the primary dependent variable is typically a measure of the rate of responding. One limitation of many traditional preclinical self-administration procedures when evaluating potential pharmacotherapies for tobacco use disorder has been the integration of control experiments that allow for a distinction to be made between drug effects that selectively decrease the rate of responding for a self-administered drug as opposed to effects that produce generalized suppression of behavior. However, self-administration studies in humans have a long history of using choice experiments to examine a variety of abused drugs, including nicotine (Johnson and Bickel, 2003; Bisaga et al., 2007; Odum and Baumann, 2007; Stoops et al., 2011; Green and Lawyer, 2014; Cassidy et al., 2015). In preclinical choice procedures, in addition to a rate-dependent measure of responding, rate-independent data about the allocation of responses for the drug as opposed to the nondrug reinforcer can also be collected (see Banks and Negus, 2017, for review). For this reason, drug versus nondrug choice experiments are becoming a more frequently used method for studying changes in preclinical self-administration behavior, although relatively few studies have used nicotine in choice paradigms to date (Lesage, 2009; Panlilio et al., 2015; Huynh et al., 2017; Bagdas et al., 2019). This may reflect a difference between nicotine and other drugs that has been noted in the human literature; although an alternative reinforcer (e.g., money) is effective for reducing cigarette smoking in humans (Bisaga et al., 2007), a meta-analysis revealed that the effectiveness of alternative options has a relatively weaker effect in studies with nicotine as compared with heroin or cocaine (Prendergast et al., 2006). However, it may also simply result from the nature of nicotine as a reinforcer that is typically not self-administered as robustly as other drugs of abuse in preclinical studies.

B. Intracranial Self-Stimulation

Intracranial self-stimulation (ICSS) is another operant procedure in which behavior is maintained by pulses of electrical brain stimulation (for review see Carlezon and Chartoff, 2007; Negus and Miller, 2014). When this procedure is used for evaluating the abuse potential of drugs, an electrode is most commonly implanted, targeting the medial forebrain bundle at the level of the hypothalamus. Following electrode implantation, the animal is trained to complete an operant response to produce an electrical stimulation that can be modified in terms of both amplitude and frequency. ICSS procedures have been performed in mice (Johnson et al., 2008; Fowler et al., 2013), rats (Schaefer and Michael, 1992; Panagis et al., 2000; Kenny et al., 2009), and nonhuman primates (Routtenberg et al., 1971) to study the ability of drugs (Negus and Miller, 2014; Freitas et al., 2016) and physiologic conditions (Freitas et al., 2015) to produce increases or decreases in baseline ICSS responding. Many drugs of abuse produce increases in measures of baseline ICSS responding; this is typically interpreted as an abuse-related effect (Bonano et al., 2014) and is correlated with alterations in dopamine signaling (Bauer et al., 2013). Furthermore, both drugs of abuse as well as drugs that do not produce abuse-related effects in animals are able to produce decreases in measures of baseline ICSS responding given sufficiently large doses; this is typically interpreted as an abuse-limiting effect (Bauer et al., 2013). Nicotine produces dose-dependent biphasic effects in ICSS, increasing responding at lower doses of nicotine and decreasing responding at higher doses (Schaefer and Michael, 1986; Huston-Lyons and Kornetsky, 1992; Bauco and Wise, 1994; Spiller et al., 2009; Freitas et al., 2016), similar to effects seen in the self-administration assay (Lau et al., 1994; Valentine et al., 1997; Le Foll et al., 2007). Thus, a favorable outcome for a potential pharmacotherapy for smoking cessation might be to attenuate nicotine-induced increases in ICSS, as seen with the N-methyl-D-aspartate receptor antagonist LY235959 (Kenny et al., 2009); however, this type of ICSS procedure is not the most commonly used for evaluating pharmacotherapies for tobacco use disorder.

An alternative ICSS procedure uses discrete trials that vary the current intensity to determine a threshold amplitude that will maintain operant responding. In these types of procedures, the reward-enhancing effects of acute nicotine are observed in the form of decreases in brain reward threshold (Bespalov et al., 1999; Nakahara, 2004; Paterson, 2009). Furthermore, following a regimen of chronic nicotine administration, both spontaneous and precipitated withdrawal produce increases in brain reward threshold, an anhedonia-like effect (Epping-Jordan et al., 1998; Bruijnzeel et al., 2007; Johnson et al., 2008). This increase in brain reward threshold is typically interpreted as diminished sensitivity to reward and decreased motivation for previously rewarding stimuli under conditions of nicotine withdrawal, and it is considered to be relevant insofar as preventing withdrawal plays an important role in successfully maintaining abstinence from smoking (Bruijnzeel and Gold, 2005; Hughes, 2006; Koob, 2008).

C. Drug Discrimination

Drug discrimination is another behavioral assay that is often used to examine compounds for abuse potential and to evaluate potential pharmacotherapies. Commonly, subjects are trained to make some response (e.g., pressing a lever) when they receive vehicle and some other response (e.g., pressing a different lever) when they receive the training dose of a drug. The training dose of the training drug then sets the occasion for responding on the drug-paired lever, and, with training, animals accurately choose the appropriate response lever even though there may be no other observable measures to indicate that they have received the training drug. In humans, a drug can be trained as a discriminative stimulus; simultaneously, subjects can be asked to respond on a variety of standardized questionnaires and rating scales (e.g., measures of “good” or “bad” drug effect) to collect subjective effects and discriminative stimulus effects simultaneously, which can be dissociable (Lamb and Henningfield, 1989). However, in humans that have been trained to discriminate nicotine from saline, the discriminative stimulus effects of nicotine are directly correlated with its subjective effects (Perkins et al., 1999).

The nicotine discriminative stimulus was one of the first studied in the operant discrimination procedure that is most commonly used today (Morrison and Stephenson, 1969). Thus, it should be no surprise that nicotine has been trained as a discriminative stimulus in a variety of species, including mouse (Gommans et al., 2000), rat (Zaniewska et al., 2006), monkey (Takada et al., 1988), and human (Perkins et al., 1996). If a test compound shares discriminative stimulus effects with nicotine, then it might serve as an effective substitution pharmacotherapy; however, there is also the potential for the test compound to have abuse liability itself.

Drug discrimination is a pharmacologically selective bioassay that was used in the past for elucidating the receptor pharmacology of nicotine in vivo (Pratt et al., 1983; Stolerman et al., 1999; Rollema et al., 2007). The nicotine cue is thought to be mediated centrally, and this is supported by the fact that a peripherally restricted nicotinic agonist, methylcarbamylcholine, does not substitute for nicotine (Desai et al., 1999). Specific brain regions can also be implicated by targeted injections of nicotine into the brain; in rats, nicotine injected into the dorsal hippocampus, but not the nucleus accumbens, produces nicotine-like discriminative stimulus effects (Shoaib and Stolerman, 1996).

One feature of drug discrimination is that the dose of the drug that is selected for training as a discriminative stimulus is known to impact the pharmacological selectivity of the resulting discrimination. For example, the discrimination of a relatively small training dose can lack pharmacological selectivity because the magnitude of the difference between the presence of a “drug effect” versus its absence is relatively small and difficult to detect. Lack of pharmacological selectivity is evidenced by substitution of test drugs with mechanisms of action distinct from the training drug. In contrast, sufficiently large training doses can result in discriminations that are relatively selective for test drugs that share a mechanism of action with the training drug [for examples with nicotine as a training drug, see Smith and Stolerman (2009) and Cunningham and McMahon (2013)].

D. Place Conditioning

Place conditioning is different from the operant assays discussed previously because it uses classic conditioning to measure preference for or avoidance of a location that has been paired with a drug stimulus. Both two- and three-chamber variations are common, in which the third chamber is a neutral, unpaired chamber that connects the first and second chambers. One of the chambers is typically paired with a dose of a drug, whereas a separate, distinct chamber is paired with the administration of the drug vehicle alone. After some number of pairings of the drug in one compartment and the absence of drug in the other, the animal is placed in the apparatus without an injection of drug or vehicle, and the amount of time spent in the two chambers previously paired with either drug or vehicle is measured. Most drugs of abuse produce a conditioned place preference. That is, animals will spend more time in the chamber previously paired with an injection of drug compared with the time they spend in the chamber previously paired with drug vehicle. Nicotine produces a place preference in both rats and mice at smaller doses (Fudala et al., 1985; Vastola et al., 2002; Walters et al., 2006) but an aversion to the place paired with larger doses of nicotine in mice, resulting in an inverted U-shaped dose-response curve (Risinger and Oakes, 1995).

One variation of this procedure is conditioned place aversion, in which instead of pairing one chamber with a drug, one chamber is paired with antagonist-precipitated withdrawal. Under these conditions, animals typically spend less time in the withdrawal-paired chamber (i.e., it is “avoided”). Conditioned place aversion studies of both mice and rats have found that adolescents, as compared with adults, have a smaller response in terms of avoidance of a chamber previously paired with nicotine withdrawal (O’Dell et al., 2007b; Jackson et al., 2009). For further review on conditioned place assays, please see Prus et al. (2009).

III. Pharmacokinetic Considerations for Evaluating Potential Pharmacotherapies

A. Absorption and Distribution

Once inhaled from a cigarette, nicotine reaches the brain within 10–20 seconds (Benowitz, 1990, 1996). This rapid rise in nicotine concentration, which allows for the titration of nicotine dose on a puff by puff basis, contributes to the high abuse liability inherent in this form of nicotine administration (Benowitz, 1990; Henningfield and Keenan, 1993).

Although nicotine is most commonly inhaled through cigarette smoke, translating this to preclinical studies has inherent difficulties. Monkeys can be taught to smoke cigarettes (Ando and Yanagita, 1981), but the variables described above limit the ability to deliver a specific, predetermined dose of nicotine via inhalation of tobacco smoke. Recent advances in technology have yielded vapor chambers for the reliable delivery of inhaled nicotine in preclinical studies. However, intravenous administration with chronic indwelling catheters remains the most common route for nicotine delivery in preclinical monkey, rat, and mouse administration procedures, in addition to extensive utilization in human studies (Goldberg et al., 1981; Spealman and Goldberg, 1982; Henningfield et al., 2016).

Nicotine delivered intravenously has 100% bioavailability compared with inhaled nicotine, 80%–90% of which is absorbed during smoking (Armitage et al., 1975). However, nicotine delivered by the intravenous route does not reach the brain as quickly as inhaled nicotine (Benowitz, 1990, 1996). Nevertheless, intravenous nicotine takes less than 60 seconds to reach the brain and provides the closest approximation of inhalation that allows for precise delivery of a specific dose. Humans report differences in the subjective effects of nicotine based on the route of administration (Henningfield and Keenan, 1993). However, of the routes of administration typically used in animal studies, only intravenous nicotine has been shown to share subjective effects with cigarette smoking in humans (Henningfield and Keenan, 1993); the subjective effects of subcutaneous nicotine in humans are modest at best (Le Houezec et al., 1993). Additionally, inhaled nicotine and intravenous nicotine follow a comparable time course in regard to onset and duration of action (Henningfield et al., 1985; Mello et al., 2013). This is opposed to subcutaneous administration of nicotine, which reaches a peak blood concentration between 20 and 25 minutes after injection in humans, although this route of administration also appears to offer 100% bioavailability (Le Houezec et al., 1993).

Solutions intended for use in ENDS that are currently available for consumers typically label nicotine content as a concentration of nicotine per total volume of liquid, and these concentrations range from 0 to 30 mg/ml. However, individual differences in inhalation variables, such as puff duration and velocity, that impact nicotine delivery from cigarettes also apply to nicotine delivered from ENDS, meaning that nicotine yield from ENDS can vary by more than 50-fold (Talih et al., 2015). Additional factors such as output voltage, other components of the nicotine solution (e.g., propylene glycol, vegetable glycerin, flavors), and the pH of the solution also impact nicotine exposure with ENDS, so it is not surprising that studies using different procedures often report different results. For example, some studies report that ENDS deliver less nicotine than a cigarette (Trehy et al., 2011; Farsalinos et al., 2013; Yingst et al., 2019) and increased latencies to reach peak nicotine concentration in blood (Farsalinos et al., 2014). Several important limitations of these studies are worth noting. First, many early studies of ENDS used experienced smokers that were relatively naïve to vaping (Schroeder and Hoffman, 2014), and it has been shown that different inhalation strategies used by naïve compared with experienced ENDS users may be responsible for lower nicotine delivery from ENDS, and once sufficiently experienced in the use of ENDS products, users may achieve higher concentrations of nicotine in blood (Farsalinos et al., 2014; Schroeder and Hoffman, 2014). Furthermore, the increased latency to peak nicotine concentration in blood may be a result of significant buccal absorption in vaping-naïve ENDS users as opposed to primarily pulmonary absorption in experienced cigarette users (Schroeder and Hoffman, 2014). More recent studies suggest that experienced ENDS users alter their inhalation strategy to achieve similar peak levels of nicotine with ENDS use as they achieve with cigarette use, independent of the concentration of nicotine solution used (St Helen et al., 2016b), and that the time course of nicotine in blood is very similar to cigarette smoking, with peak nicotine concentrations within 2–5 minutes of vaping (St Helen et al., 2016a). However, even if ENDS users receive similar amounts of nicotine, the absence of toxins present in combusted smoke have led to the generally accepted conclusion that ENDS are less harmful than cigarettes (https://www.cdc.gov/tobacco/basic_information/e-cigarettes/about-e-cigarettes.html), although they are not approved pharmacotherapies for smoking cessation. Studies in rats have found that experimental vapor chambers reliably produce air-nicotine concentrations of 4–12 mg/m3 and that within 60 minutes of exposure, animals have levels of nicotine in blood equivalent to the average concentration observed in human smokers (Gilpin et al., 2014).

All formulations of FDA-approved nicotine replacement therapy are absorbed more gradually than either inhaled or intravenous nicotine, resulting in slower increases in nicotine blood levels (Henningfield et al., 1985; West et al., 2000). This more gradual increase in nicotine concentration results in lower relative abuse liability, as slower absorption produces modest increases of dopamine over time in key areas of the brain related to substance use disorders in contrast to the corresponding quick spike of dopamine release and subsequent downstream signaling events produced by cigarette smoking (Dani and De Biasi, 2001; Nestler, 2005). Evidence suggests that simultaneous smoking may slow transdermal absorption, as was found to be the case when nicotine was administered intravenously to nicotine patch wearers (Benowitz et al., 1992). Thus, absorption kinetics, as opposed to simply absorption route, is a critical factor in determining the therapeutic potential of a nicotine replacement strategy.

Nicotine absorption is dependent on the pH of the vehicle used for administration as well as the environment it is administered into (e.g., liquid of the oral cavity for buccal absorption) (Le Houezec, 2003; Hukkanen et al., 2005; U.S. Department of Health and Human Services, 2010; Pickworth et al., 2014). However, once nicotine is in the bloodstream at a physiologic pH, it is distributed extensively to body tissues. In autopsies of smokers, the highest affinity for nicotine was found in the liver, kidney, spleen, and lung, and the lowest was found in adipose tissue (Hukkanen et al., 2005).

The time course of nicotine, its accumulation in various organs of the body, and its pharmacologic effects are highly dependent on the route of administration and rate of dosing. The concentration of nicotine in blood after smoking a cigarette can reach 100 ng/ml but is generally in the range of 20–60 ng/ml (Armitage et al., 1975; Henningfield and Keenan, 1993; Gourlay and Benowitz, 1997; Rose et al., 1999; Lunell et al., 2000). Blood levels of nicotine peak after smoking a cigarette and fall rapidly over the subsequent 20 minutes; the average distribution half-life of nicotine is about 8 minutes (Hukkanen et al., 2005). Over the course of a day, smokers typically demonstrate trough concentrations of nicotine in blood from 10 to 35 ng/ml and peak concentrations between 20 and 50 ng/ml (Schneider et al., 2001). The average elimination half-life of nicotine in plasma is the same for both inhaled and intravenous nicotine, approximately 100–150 minutes (Benowitz and Jacob, 1993, 1994). Thus, typical patterns of cigarette smoking result in considerable accumulation of nicotine over the course of a day, which then diminishes overnight, resulting in very low nicotine levels upon waking in the morning.

Nicotine present in saliva is often used as a convenient proxy for the amount of nicotine present in blood. However, in nicotine skin patch users, nicotine in saliva was a factor of 8.13-times greater than nicotine in plasma (Rose et al., 1993). This accumulation is likely due to ion trapping of nicotine in saliva when in ionized form (Hukkanen et al., 2005).

B. Metabolism and Elimination

Metabolism of nicotine takes place primarily in the liver, and nicotine has six primary metabolites, although numerous others have also been identified, including cotinine, trans-3-hydroxycotinine, nicotine N-oxide, nornicotine, norcotinine, and cotinine N-oxide (Hukkanen et al., 2005). Cotinine is the primary metabolite in both humans and nonhuman primates; 70%–80% of nicotine is metabolized to cotinine in the liver in humans (Benowitz and Jacob, 1994), whereas rhesus macaques metabolize 80% of nicotine to cotinine (Poole and Urwin, 1976). Mice, rabbits, and dogs also metabolize nicotine into cotinine at a rate similar to humans and nonhuman primates. However, rats and guinea pigs metabolize nicotine equally into nicotine-N-oxide, cotinine, and trans-3-hydroxycotinine (Matta et al., 2007). Cotinine and trans-3-hydroxycotinine are the primary metabolites identified in urine for all mammalian species studied to date (Jenner et al., 1973; Nwosu and Crooks, 1988; Kyerematen et al., 1990). Half-lives of nicotine and cotinine appear to be similar in humans and macaques (Seaton et al., 1991). The half-life of nicotine is generally 45 minutes in rats and between 6 and 7 minutes in mice. This is considerably shorter than the 2-hour half-life of nicotine observed in humans and nonhuman primates (Matta et al., 2007). Thus, an important consideration for nicotine studies in rodents is that a higher dose of nicotine is needed to achieve equivalent human physiologic levels.

The enzyme responsible for both metabolism of nicotine to cotinine and cotinine to trans-3-hydroxycotinine in both humans and rhesus monkeys is CYP2A6 (Murphy et al., 1999; Hecht et al., 2000; Hukkanen et al., 2005). In mice, CYP2A5 is the functional homolog of human CYP2A6. In rats, CYP2A6 is inactive. Instead, CYP1B1/2 is the enzyme responsible for nicotine metabolism (Hammond et al., 1991; Nakayama et al., 1993). Additionally, cigarette smoking is known to accelerate the metabolism of some drugs (Zevin and Benowitz, 1999), although it appears to slow the metabolism of nicotine itself (Benowitz and Jacob, 1993). In humans, differences in metabolism based on both ethnicity and sex have been reported, including faster nicotine and cotinine clearance in women than in men (Pérez-Stable et al., 1998; Hukkanen et al., 2005; Benowitz et al., 2006, 2009; Tanner et al., 2015).

Cotinine has a longer elimination half-life than nicotine, averaging about 770–1130 minutes (Benowitz and Jacob, 1994), but the elimination half-life of trans-3-hydroxycotinine falls between nicotine and cotinine at about 400 minutes (Benowitz and Jacob, 2001). The longer elimination half-life of cotinine relative to nicotine results in less variability in cotinine concentrations measured over the course of the day. This has resulted in the wide-spread use of cotinine concentration as a biomarker for daily tobacco consumption (Benowitz et al., 1996), and several studies have demonstrated that experienced ENDS users achieve levels of cotinine similar to cigarette smokers (Etter and Bullen, 2011; Caponnetto et al., 2013). Furthermore, the ratio of trans-3-hydroxycotinine to cotinine present in plasma or saliva can be used as a marker of CYP2A6 activity (Dempsey et al., 2004). A genetic polymorphism in the CYP2A6 gene results in individuals who may be broadly categorized as fast or slow metabolizers, and this ratio is a predictor of cigarette consumption (Benowitz et al., 2003).

Nonrenal clearance accounts for the majority of nicotine elimination. Renal clearance is, on average, about 35–90 ml/min, which accounts for about 5% of total nicotine clearance (Hukkanen et al., 2005).

IV. Pharmacodynamic Considerations for Evaluating Potential Pharmacotherapies

A. Receptor Pharmacology

Acetylcholine is the endogenous neurotransmitter for acetylcholine receptors, which fall into two major groups: nAChRs and muscarinic acetylcholine receptors (mAChRs) (Albuquerque et al., 1995; Gotti and Clementi, 2004; Eglen, 2005; Dani and Bertrand, 2007). Muscarinic receptors are metabotropic, G protein-coupled seven transmembrane receptors that were originally defined with activation by muscarine, a product of the Amanita muscaria mushroom (Eugster et al., 1965). There are five subtypes, labeled M1 through M5 (Hulme et al., 1990; Fredriksson et al., 2003). Like nicotinic receptors, mAChRs are located both centrally and in the periphery on neuronal and nonneuronal cells. However, in comparison with nicotinic receptors, which are rapidly activated (i.e., microseconds), activation of mAChRs is generally slower (i.e., milliseconds). For a review of mAChR pharmacology, see Kruse et al. (2014). Although there is no evidence that nicotine binds to muscarinic receptors, effects mediated by muscarinic receptors may be an important consideration in the development of potential pharmacotherapies that target endogenous acetylcholine.

Nicotinic receptors are ionotropic, ligand-gated ion channels that were originally defined by activation with nicotine, an alkaloid produced by plants in the nightshade family, but traditionally associated with plants of the genus Nicotiana, otherwise known as tobacco plants. Nicotinic receptors are composed of five subunits (Cooper et al., 1991), which, together, form a pore in the cell membrane that allows for the passage of ions in and out of the cell.

Nicotinic receptors can be generally divided into two populations: muscle-type and neuronal. Muscle-type nAChRs were identified first and are found at the neuromuscular junction, where ion conductance through the channel produces excitatory postsynaptic potentials that are characteristic of muscle contraction. Neuronal nAChRs can be further subdivided into those that serve the autonomic nervous system (i.e., ganglionic) and those that are present in the brain (i.e., central). Like muscle-type nAChRs, ganglionic nAChRs are generally located postsynaptically and transmit fast excitatory postsynaptic potentials that are often the first signal in a serial circuit followed by slow excitatory postsynaptic potentials mediated by mAChRs. Compounds restricted to the periphery by poor penetration of the blood-brain barrier act selectively at these receptors, and ganglionic receptors may be responsible for some side effects of cholinergic drugs.

Nicotinic receptors in the brain are of primary interest for the study of tobacco use disorder. Like muscle-type and ganglionic receptors, nicotinic receptors in the brain are ligand-gated ion channels composed of five subunits (Fig. 1A). The subunits that have been identified in mammalian brain are notated as α2 through α7 and β2 through β4. Although in theory, many different possible combinations of subunits could come together to form an ion channel, there are apparent limitations. One of these limitations is that certain α subunits are required for a functional binding site; thus, the β subunits are sometimes referred to as accessory subunits. Both homomeric subtypes, which include five of the same α subunit and heteromeric subtypes, containing both α and β subunits, have been identified. In mammalian brain, homomeric receptors are thought to be limited to those containing five α7 subunits, whereas several distinct heteromeric subtypes have been identified, each with different pharmacological characteristics (Fig. 1B). Although they serve distinct functions, nicotine binds to all subtypes of nAChRs in the brain; however, the affinity of nicotine for the nAChR varies by subtype.

Fig. 1.
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Fig. 1.

Basic structure of neuronal nAChRs. (A) A nAChR is composed of five subunits. Each subunit contains four transmembrane domains (M1–M4). An amine functional group is located at the end of the M1 transmembrane domain, whereas a carboxyl group is located at the end of the M4 transmembrane domain (insert). When an agonist (e.g., acetylcholine, nicotine) binds an orthosteric site, extracellular sodium and calcium enter the cell. (B) Diagram of the pentameric structure of neuronal nAChRs, which can be heteromeric (e.g., α4β2, α4α5β2) or homomeric (e.g., α7) in composition.

1. α4β2* Nicotinic Acetylcholine Receptors

The most prevalent nAChR subtype in the mammalian brain is the heteromeric α4β2* subtype (in which * denotes the possible involvement of additional subunits), which binds nicotine with high affinity (Whiting and Lindstrom, 1987; Flores et al., 1997; Zoli et al., 2002). There is abundant evidence that the α4β2* subtype is of particular importance to the abuse potential of nicotine (Corrigall et al., 1992; Picciotto et al., 1998; Tapper et al., 2004; Maskos et al., 2005; Besson et al., 2006; Ikemoto et al., 2006; Gotti et al., 2010). For example, studies have shown that β2 knockout mice do not self-administer nicotine in the absence of the β2 subunit; however, when β2 subunit functionality is returned to these mice, they begin to self-administer nicotine (Picciotto et al., 1998). Also, α4 knockout mice do not acquire nicotine self-administration (Pons et al., 2008) in addition to expressing fewer nicotine binding sites and a significant decrease of nicotine binding in the brain (Marubio et al., 1999; Ross et al., 2000). Furthermore, in rats, compounds that act as partial agonists at the α4β2* subtype have been shown to decrease the acquisition, expression, and reinstatement of nicotine’s effects in the place preference assay (Biala et al., 2010); to reverse nicotine-induced facilitation of intracranial self-stimulation (Vann et al., 2011); and to reduce nicotine withdrawal–induced increases in intracranial self-stimulation thresholds (Igari et al., 2014).

Individual assemblies of the α4β2* subtype may or may not contain an accessory subunit (e.g., α5). In those that do not contain an accessory subunit, combinations of α4 and β2 subunits occur in ratios of 3:2 and 2:3. Both of these combinations are expressed in recombinant receptors, and this ratio determines receptor affinity and sensitivity to ligands (Bertrand and Terry, 2018). Of note, although different potencies and binding affinities are reported, both nicotine and varenicline bind to α4β2* nAChRs with both subunit ratios (Moroni et al., 2006; Anderson et al., 2009). However, it has yet to be determined if targeting high [i.e., (2) α4 plus (3) β2 subunit] or low [i.e., (3) α4 plus (2) β2 subunit] nAChRs is more beneficial for the development of smoking-cessation pharmacotherapies.

Of α4β2* nAChRs containing an accessory subunit, those containing the α5 subunit [i.e., (α4β2)2α5] are important in the brain and account for between 10% and 37% of total α4β2* nAChRs, depending on the brain region (Brown et al., 2007; Mao et al., 2008). Interestingly, a single nucleotide polymorphism found in the human gene encoding the α5 subunit results in decreased (α4β2)2α5 function, and this has been linked to an increased vulnerability to tobacco use disorder (Bierut et al., 2008; Kuryatov et al., 2011). Studies in mice lacking functional α5 subunits found that α5 knockout mice show significant decreases of nicotine binding in the brain as well as dysfunction of dopamine transmission regulated by α4β2* nAChRs in the striatum (Exley et al., 2012; Besson et al., 2016). Furthermore, the self-administration of nicotine by α5 knockout mice is increased compared with controls, and this effect can be reversed by re-expression of the α5 subunit in medial habenula (Fowler et al., 2011). This increase was only apparent at high doses of nicotine, however, and given the role of the habenula in regulating avoidance of noxious substances (Donovick et al., 1970), further evidence supported a role for (α4β2)2α5 nAChRs in the medial habenula-interpeduncular nucleus pathway mediating negative effects of nicotine that limit its intake (Fowler et al., 2011). Similar effects were seen in a nicotine conditioned place preference assay, in which low nicotine doses induced a preference in both wildtype and α5 knockout mice, but high doses only induced a preference in knockout mice (Jackson et al., 2010). Furthermore, nAChRs containing the α5 subunit, unlike other α4β2* nAChRs, which are highly upregulated as a result of chronic nicotine treatment, show no such change in expression (Mao et al., 2008).

Based on our current understanding of nicotinic receptor subtypes and the accumulation of clinical and preclinical evidence, many experts believe that pharmacotherapies for smoking cessation are likely to be most effective if they selectively target the α4β2* subtype of nAChR. However, as substance use disorders are highly complex, medications targeting other nAChR subtypes may also be relevant and have been explored for their potential utility in treating tobacco use disorder.

2. α7 Nicotinic Acetylcholine Receptors

The second most prevalent nAChR subtype in the brain is the homomeric α7 subtype, which binds nicotine with low affinity (Wada et al., 1989; Anand et al., 1991; Flores et al., 1997). The α7 nAChR subtype seems to play an important part in both cognitive function (Pichat et al., 2007; Roncarati et al., 2009; Wallace et al., 2011) and inflammation (Alsharari et al., 2013; Egea et al., 2015). There is also evidence that this receptor subtype plays some role in the reinforcing effects of nicotine, as rats self-administered significantly less nicotine after administration of an antagonist that prevented nicotine from interacting with α7-containing nAChRs (Markou and Paterson, 2001) despite evidence that α7 knockout mice self-administer nicotine to the same extent as controls (Pons et al., 2008). Furthermore, modulation of dopamine signaling by α7-containing nAChRs may also play a role in tobacco use disorder (Kaiser and Wonnacott, 2000), and additional studies indicate that α7-containing nAChRs may be important in the somatic signs of nicotine withdrawal (Jackson et al., 2018). Despite this, α7 nAChRs do not appear to be necessary for the nicotine discriminative stimulus, as α7 knockout mice can be readily trained to discriminate nicotine from saline (Stolerman et al., 2004). There are species differences in nAChR density and distribution that should be considered in interpreting these studies and their translational relevance. For example, the α7 subtype is more widely distributed in the primate brain (Papke et al., 2005) than it is in the rodent brain (Papke and Porter Papke, 2002) and thus might be expected to differentially mediate the effects of nicotine in primates and rodents.

3. Other Nicotinic Acetylcholine Receptor Subtypes

With respect to behavioral effects of nicotine, there is evidence that other subtypes of nAChR may also play an important role. It has been found that nAChRs containing α3β4 subunits mediate some effects of nicotine. Specifically, receptors containing these subunits can mediate seizure and hypolocomotor effects of nicotine in mice (Salas et al., 2004a). A partial agonist at nAChRs containing α3β4 was found to decrease reinstatement of nicotine seeking in a rat model of stress-induced relapse (Yuan et al., 2017). Furthermore, mice lacking the β4 subunit display a decrease in behaviors associated with nicotine withdrawal (Salas et al., 2004b). It is likely that some of these other receptor subunits are part of heteromeric receptors containing the α4 and β2 subunits, but the extent to which this may be the case is not clear. For example, small molecule antagonists have been developed that selectively reduce the activity of nAChRs containing the α6 subunit; however, this includes both heteromeric receptors of the α4β2* type as well as other receptors containing the α6 subunit. In rats, this manipulation dose-dependently decreased nicotine self-administration, suggesting a potential role for the α6 subunit in the reinforcing effects of nicotine (Dwoskin et al., 2009).

4. Antagonists as Pharmacological Tools

The use of nAChR antagonists as pharmacological tools has offered insight into the role of nAChR subunits and the pharmacological profile of nicotine’s effects as well as provided further evidence for central mediation of the nicotine discriminative stimulus. Specifically, antagonists restricted to the periphery by poor blood-brain barrier penetration, such as hexamethonium and chlorisondamine, fail to antagonize the nicotine discriminative stimulus (Hazell et al., 1978; Stolerman et al., 1984, 1988; Besheer et al., 2004; Palmatier et al., 2004). Notably, when chlorisondamine is administered intracerebroventricularly (i.e., precluding the need to cross the blood-brain barrier), it produces persistent antagonism of the nicotine discriminative stimulus for several weeks (Kumar et al., 1987). Atropine, a muscarinic acetylcholine receptor antagonist, does not antagonize the discriminative stimulus effects of nicotine in rodents (Rosecrans, 1989), although it did antagonize the discriminative stimulus effects of a relatively large (1.78 mg/kg, s.c.) dose of nicotine in monkeys (Moerke and McMahon, 2019). Furthermore, several brain-penetrant nAChR antagonists with varying subunit selectivity are commonly employed in pharmacological studies of nicotine and nAChRs.

Mecamylamine is a relatively nonselective, noncompetitive antagonist of nAChRs (Papke et al., 2001; Cunningham et al., 2014). It was initially approved in humans for use in the treatment of hypertension, although it is now rarely used for this purpose (Shytle et al., 2002). It functions as a channel blocker of all nAChRs, including both the α4β2* and the α7 subtypes of nAChR (Varanda et al., 1985), which are the two most prevalent subtypes present in the brain. Mecamylamine blocked the discriminative stimulus effects of nicotine in mice (Stolerman et al., 1999), rats (Morrison and Stephenson, 1969; Jutkiewicz et al., 2011), and monkeys (Cunningham et al., 2016; Moerke et al., 2017). Although mecamylamine has been investigated as a stand-alone or adjunct treatment of smoking cessation (Rose et al., 1989, 1994, 1998), it is generally thought that compliance and compensatory smoking would limit its effectiveness in treating tobacco use disorder (Rose et al., 1989). More recently, evidence from rodent models of depression-like behavior have suggested its potential use for depression (Popik et al., 2003; Rabenstein et al., 2006; Andreasen et al., 2009), although phase III trials of a mecamylamine enantiomer did not support translation for use as an antidepressant medication in humans (Moller et al., 2015).

Pempidine (1:2:2:6:6-pentamethylpiperidine) is a brain-penetrant noncompetitive cholinergic receptor antagonist originally developed for the treatment of hypertension; however, it has largely been replaced by newer drugs with greater specificity and fewer side effects (Corne and Edge, 1958; Klowden et al., 1978). Pempidine is able to produce full antagonism of nicotine’s physiologic effects (Haikala and Ahtee, 1988; Martin et al., 1990). Additionally, in both rats (Garcha and Stolerman, 1993) and monkeys (Cunningham et al., 2019) trained to discriminate mecamylamine, pempidine produced full substitution in the drug discrimination assay, further supporting the characterization of pempidine as a functional nonselective nAChR antagonist.

Dihydro-β-erythroidine (DHβE) is a competitive antagonist selective for nAChRs containing the β2 subunit in vitro (Williams and Robinson, 1984; Mansvelder et al., 2002), and can be used as a tool in vivo to examine effects mediated by these receptors. Antagonism of the discriminative stimulus effects of nicotine by DHβE has been demonstrated in mice, rats, and rhesus monkeys (Stolerman et al., 1997; Gommans et al., 2000; Shoaib et al., 2000; Moerke et al., 2017). However, there is also evidence from the literature for differential antagonism of nicotine by DHβE dependent on the size of the training dose (Stolerman et al., 1997; Jutkiewicz et al., 2011). Specifically, DHβE does not consistently antagonize the discriminative stimulus effects of nicotine in rodents (Shoaib et al., 2000; Jutkiewicz et al., 2011) or in monkeys (Cunningham et al., 2012). These results have been interpreted as evidence that, while the discriminative stimulus effects of a small training dose of nicotine are mediated by α4β2* nAChRs, the discriminative stimulus effects of a larger training dose of nicotine recruit other nAChR subtypes in addition to α4β2*. As with mecamylamine, DHβE has been found to produce antidepressant-like effects in rodents (Popik et al., 2003; Rabenstein et al., 2006; Andreasen et al., 2009); however, to our knowledge, it is not currently under development for this purpose.

Methyllycaconitine (MLA) was originally isolated from Delphinium brownie and is a competitive antagonist selective for the α7 nAChR subtype (Alkondon et al., 1992; Mogg et al., 2002; Stegelmeier et al., 2003). MLA does not antagonize the nicotine discriminative stimulus in rhesus monkeys (Moerke et al., 2017), rats (Zaniewska et al., 2006), or mice (Gommans et al., 2000), even when MLA is administered via the intracerebroventricular route (Brioni et al., 1996). It has been suggested for use in treating cannabis dependence (Weinstein and Gorelick, 2011) and cancer (Wu et al., 2011), and it did reduce self-administration of nicotine in rats (Markou and Paterson, 2001). However, it is unlikely to be used for any of these purposes in humans without further development, as it is highly toxic in sufficient doses (Nation et al., 1982). Results described above from preclinical studies using nicotine self-administration and nicotine discrimination assays are summarized in Table 1.

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TABLE 1

Summary of results from nicotinic and nonnicotinic compounds studied in nicotine self-administration and drug discrimination

B. Tolerance

There are three different types of drug tolerance: pharmacokinetic, pharmacodynamic, and behavioral. Tolerance is said to occur when a larger dose of drug is required to achieve the same level of effect previously achieved by a smaller dose of the drug or when the same dose of drug produces a smaller magnitude of effect with subsequent administration. Tolerance to the effects of abused drugs often occurs in individuals with substance use disorders, but tolerance itself is not indicative of substance use disorder. In the context of the current review, the word “tolerance” will be used exclusively to describe pharmacodynamic tolerance to effects of nicotine. Importantly, nicotine produces at least two distinct types of tolerance: chronic tolerance, which develops over a period of days and can be observed in experienced smokers even following a period of abstinence, and acute tolerance, which develops over a period of minutes to hours. In clinical studies, it is generally presumed that chronic tolerance has developed in habitual smokers, allowing for comparisons to be made between groups both with (i.e., smokers) and without (i.e., nonsmokers) chronic tolerance to nicotine (Perkins et al., 1993). Acute tolerance, on the other hand, occurs as rapidly as after one dose of nicotine (Stolerman et al., 1973) and clinically can be observed in both experienced smokers as well as nicotine-naïve individuals (Perkins et al., 1993). Evidence suggests that both acute and chronic tolerance to nicotine are important considerations in the development of pharmacotherapies for tobacco use disorder (Balfour, 1994; Benowitz, 2008).

Nicotine in the context of cigarette smoking is typically dosed repeatedly at semiregular intervals over the course of the day. This leads to cycles of receptor activation and desensitization, and accumulating evidence suggests that both states contribute to the reinforcing effects of cigarette smoking [see Picciotto et al. (2008) for review]. This pattern of behavior is generally disrupted overnight, when sleeping precludes continued nicotine dosing and leads to a period of nighttime abstinence, with subsequent withdrawal symptoms occurring when waking in the morning. Thus, the first cigarette is smoked on a baseline that differs from every other cigarette during the day.

Acute tolerance to the subjective effects of nicotine is thought to be responsible for the finding that smokers report the first cigarette of the day as the most pleasurable (Fant et al., 1995). Experimentally, acute tolerance to effects of nicotine has been examined in both monkeys and humans, and there is evidence for tolerance to both physiologic (e.g., cardiovascular) effects of nicotine (Perkins et al., 1991) as well as the discriminative stimulus effects of nicotine (Perkins et al., 1996; Moerke and McMahon, 2018) and the subjective effects of nicotine (Perkins et al., 1993). Furthermore, acute tolerance to the subjective effects of nicotine is reported both in smokers and subjects who have never smoked (Perkins et al., 1993), although these two groups rate the subjective effects of nicotine differently.

However, tolerance to effects of nicotine that develops over days and years has historically been of more interest for the purpose of developing pharmacotherapies for the treatment of tobacco use disorder (Kauer and Malenka, 2007; Kalivas et al., 2009). Thus, chronic tolerance to the effects of nicotine on locomotor activity has been studied extensively in rodents (Keenan and Johnson, 1972; Stolerman et al., 1973, 1974; Hubbard and Gohd, 1975; Hatchell and Collins, 1977; Clarke and Kumar, 1983a,b; Marks et al., 1983, 1985), and chronic tolerance to the subjective effects of nicotine has been studied in humans (Perkins et al., 1993, 1994, 2002). Although the precise mechanisms underlying tolerance to locomotor activity and subjective effects of nicotine remain unclear, it has long been known that nicotine receptor binding is increased in the brains of animals after chronic exposure to nicotine (Marks et al., 1983; Schwartz and Kellar, 1983; Sanderson et al., 1993) as well as in human smokers compared with nonsmokers (Benwell et al., 1988; Breese et al., 1997; Court et al., 1998; Perry et al., 1999). Indeed, receptor upregulation is considered one hallmark of chronic tolerance to nicotine (Benwell et al., 1988; Cairns and Wonnacott, 1988). This is in opposition to what is typically observed after chronic drug treatment, which is downregulation of receptors (Overstreet and Yamamura, 1979; Creese and Sibley, 1981). Currently, this exception to the general rule is thought to be related to nicotine’s ability to inactivate nAChRs (Marks et al., 1983; Schwartz and Kellar, 1985).

In vitro studies suggest that upregulation of nicotinic receptors varies based on the subtype of receptor. Whereas the α4β2* subtype is readily upregulated after nicotine exposure, the α3β4 subtype is upregulated to a lesser degree. Furthermore, the α4β2* subtype appears to recover more slowly from upregulation than does the α3β4 subtype (Peng et al., 1994; Wang et al., 1998; Fenster et al., 1999; Meyer et al., 2001; Harkness and Millar, 2002). Evidence for this difference has been demonstrated in vivo as well. In rats treated with nicotine for 14 days, upregulation of α4β2* binding sites was shown to be between 20% and 100%, depending on brain region; however, similar upregulation of α3β4 receptors was not apparent (Nguyen et al., 2003).

Interestingly, altered transcription does not seem to play a role in this receptor upregulation, as mRNA levels remain constant over time with nicotine exposure (Marks et al., 1992; Peng et al., 1994; Ke et al., 1998). Furthermore, chronic treatment with nicotine does not appear to modify metabolism (Hatchell and Collins, 1977; Marks et al., 1983). In preclinical rodent studies of chronic tolerance, 1 mg/kg nicotine administered twice daily for 5 days is sufficient for receptor upregulation to reach its half-maximal state (Marks et al., 1985; Schwartz and Kellar, 1985).

The subjective effects of nicotine in cigarette smokers are influenced by both chronic and acute tolerance to nicotine. By extension, the subjective effects of nicotine differ as a function of duration of abstinence and thus are likely to change over the course of smoking-cessation treatments. For example, both chronic and acute nicotine tolerance can lead to decreases in some subjective measures of smoking. As mentioned above, nicotine acts as an array of nicotinic receptors and has a wide range of physiologic effects. Also, as mentioned above, selective targeting of specific nAChR subtypes is common in the development of pharmacotherapies for smoking cessation. Thus, an agonist at α4β2* used as a smoking-cessation pharmacotherapy may produce tolerance to the effects of nicotine that are mediated by α4β2* and may or may not alter nicotine’s actions at other nAChR subtypes (de Moura and McMahon, 2017). Furthermore, both acute and chronic tolerance will alter the effectiveness of treatments for smoking cessation, insomuch as these treatments are or are not affected by cross-tolerance. Thus, these factors must be considered when evaluating potential pharmacotherapies for tobacco use disorder.

C. Physiologic Dependence and Withdrawal

Although substance use disorders are often associated with the positive subjective effects of the abused drug, continued drug use can also be motivated by the desire to avoid negative effects associated with drug withdrawal. Discontinuation of nicotine use in dependent individuals leads to increases in stress, appetite, insomnia, anxiety, and irritability as well as disruptions in cognition (Hughes, 2007; American Psychiatric Association, 2013; Wesnes et al., 2013). Many pharmacotherapies for smoking cessation attenuate the withdrawal effects of nicotine discontinuation, and this is thought to be one important aspect of their effectiveness. Experimental paradigms in rodents and nonhuman primates can recapitulate many of the symptoms associated with nicotine withdrawal in humans, such as increases in stress-like, anhedonia-like, and anxiety-like behaviors and disruptions in learned memory tasks (Malin et al., 1994; De Biasi and Salas, 2008). For example, nicotine withdrawal in rats was found to increase corticotropin-releasing factor levels in the central nucleus of the amygdala, an area of the brain known to modulate stress response (George et al., 2007). Furthermore, nicotine withdrawal increased anxiety-like behavior through activation of a subset of corticotrophin-releasing factor receptors. Of note, repeated exposure to inhaled nicotine vapor (as with ENDS), upon abrupt discontinuation, produces signs of tobacco use disorder and withdrawal in both humans (Morean et al., 2018) and rodents (George et al., 2010, 2011). Clinically, the reported severity of nicotine withdrawal effects by smokers is a potential predictor of relapse (West et al., 1989). Thus, an additional consideration in developing potential pharmacotherapies for smoking cessation is the treatment of nicotine withdrawal–related effects.

V. U.S. Food and Drug Administration–Approved Pharmacotherapies for Smoking Cessation

It is estimated that 70%–80% of current cigarette smokers want to quit smoking, and many of them have made at least one quit attempt in the last year (Schuckit et al., 1994; U.S. Department of Health and Human Services, 2014; Babb et al., 2017). However, a recent study suggested that most current smokers will try to quit, on average, 30 times or more before being successful (Chaiton et al., 2016). In fact, most attempts to quit fail within the first week (Hughes et al., 2004). In the United States, at least 40% of smokers attempt to quit smoking each year (Hughes et al., 2004), but even with behavioral and pharmacotherapies, fewer than 5% remain abstinent for more than 3 months (U.S. Department of Health and Human Services, 2014). In the United States, there are three first-line pharmacotherapies approved by the FDA for smoking cessation: nicotine replacement therapy, varenicline, and bupropion.

A. Nicotine Replacement Therapies

In the United States, nicotine replacement is the most widely available and easily accessible pharmacotherapy for smoking cessation, as most formulations can be purchased over the counter and without a prescription. Nicotine replacement was added to the WHO List of Essential Medicines in 2009, and a wide variety of nicotine replacement products are marketed around the world. There are a number of legal and regulatory differences between countries as well as differences in attitude about nicotine replacement as a harm-reduction measure; thus, the availability (i.e., by prescription only or from a pharmacy) of different formulations varies from country to country. For example, nicotine gum (Nicorette), the first nicotine replacement therapy approved by the FDA for use in the United States in 1984, was originally available by prescription only. Similarly, the transdermal nicotine patch (NicoDerm CQ), approved by the FDA in 1991, originally required a prescription. These formulations only became available “over the counter” in the U.S. in 1996, when nicotine nasal spray (Nicotrol NS), followed by the nicotine inhaler (Nicotrol), became available by prescription. The nicotine lozenge (Commit), approved in 2002, was the only nicotine replacement therapy that never required a prescription in the United States. ENDS started appearing on the market around 2003, and use in the United States and elsewhere has grown dramatically in recent years; however, there is no current consensus on the safety or efficacy of these products, so regulations vary widely. In the United States, they are regulated by the FDA and are legal to buy for anyone 18 years of age or older; however, they are not considered a pharmacotherapy for smoking cessation.

One nicotine reduction strategy was part of an effort by tobacco companies to lower perceived harm of their product by marketing so-called “light” cigarettes. Although low-yield nicotine cigarettes are considered attractive measures for decreasing nicotine consumption (Benowitz and Henningfield, 1994), these products were primarily intended to reduce nicotine content with filter ventilation, not by changing the nicotine content of the tobacco used in cigarettes. Furthermore, for these types of cigarettes, evidence suggests that smokers will alter variables of nicotine intake, including puff volume, depth of inhalation, extent of dilution with room air, rate of puffing, and intensity of puffing, to compensate (U.S. Department of Health and Human Services, 1981). More recently, this approach has been revived by researchers studying low-yield nicotine cigarettes in clinical trials, indicating that cigarettes with reduced nicotine content do have potential for use in smoking-cessation treatments (Hatsukami et al., 2010; Donny et al., 2015; Pacek et al., 2016; Tidey et al., 2017), but this strategy is not currently approved by the FDA.

Nicotine replacement therapies, regardless of formulation, work on the same principle executed slightly differently; they promote smoking cessation because they are substitution therapies, continuing to provide nicotine by another route of administration and without other tobacco constituents after an individual has quit using tobacco. These therapies are aimed at reducing tobacco cravings and withdrawal symptoms by delivering therapeutic doses of nicotine that generally have a slower onset and are thus less likely to be abused than inhaled nicotine. Furthermore, nicotine is delivered without the additional toxins that are inhaled along with tobacco smoke. With the exception of the nicotine patch, which delivers nicotine at a constant low rate, these formulations can be taken on an as-needed basis, although they do have recommended dosing regimens. Ideally, an individual will taper the magnitude of the dose of nicotine they are self-administering, as nicotine replacement is only intended to be used for 2–3 months. This is one potential drawback to nicotine replacement therapy, as many people find themselves unable or unwilling to gradually decrease their dose and continue long-term use (Hajek et al., 1988; Hughes et al., 1991; Johnson et al., 1991; Hurt et al., 1995). Despite this pattern of behavior, studies to date have not examined the effects of these pharmacotherapies over extended periods of time, so the relative safety of long-term use of nicotine replacement therapies is unknown. Additionally, even among patients receiving a prescription for a product available over the counter (i.e., nicotine patch, nicotine gum), only 67% are given any instructions for usage by their physician, and 77% receive no follow-up (Shiffman et al., 2007). Nicotine replacement therapies may also produce side effects, such as insomnia, dizziness, and headaches, that compromise compliance (Jorenby et al., 1995; Hurt et al., 1998; Hajek et al., 1999) as well as have the potential for nicotine toxicity at large doses (Dale et al., 1995).

Despite these potential disadvantages, nicotine replacement therapies generally appear to approximately double a smoker’s chance of remaining abstinent 6 months after quitting over placebo, and there do not appear to be differences among the different formulations (Cahill et al., 2013). However, a conflicting report suggests that after properly adjusting for bias, there is no indication that use of any nicotine replacement formulation improves outcomes for smoking cessation over placebo (Stanley and Massey, 2016). This claim does not extend to findings that suggest that using two nicotine replacement therapies in combination appears to be about twice as effective as using any one of the formulations alone (Cahill et al., 2013, 2014). The benefit of combining two different forms of nicotine replacement therapy is similar to what has been reported for varenicline alone.

B. Varenicline (Chantix)

Varenicline is a novel compound developed specifically for use in smoking cessation. Approved by the FDA in 2006, varenicline is only available by prescription. The recommended course of treatment is to begin taking varenicline a week before planning to quit smoking. For the first 3 days, 0.5 mg is taken as a tablet once per day and then twice per day for the rest of that week. At this point, when no longer smoking, the dose is increased to 1 mg twice daily for an additional 12 weeks. This course of treatment can be repeated or extended for those who relapse. Varenicline was identified among a series of compounds synthesized based on the structure of cytisine, a natural compound and partial nAChR agonist marketed for smoking cessation in Europe as Tabex (Coe et al., 2005). Like cytisine, it is designated as a partial, or low-efficacy, agonist. Theoretically, as a partial agonist, varenicline is effective as a pharmacotherapy for smoking cessation in two complimentary ways: 1) it functions as a substitution therapy like nicotine replacement, reducing cravings and withdrawal effects; 2) it also functions as an antagonist therapy, reducing or preventing the reinforcing effects of tobacco if an individual continues to smoke while taking it (Coe et al., 2005).

Electrophysiological studies in transfected cells demonstrate that varenicline does not produce the same maximum effect as nicotine at α4β2* nAChRs (Coe et al., 2005; Rollema et al., 2007). Furthermore, varenicline antagonizes nicotine’s effects at this receptor subtype (Coe et al., 2005). Varenicline also demonstrates lower efficacy than nicotine to stimulate dopamine release from rat brain slices (Rollema et al., 2007). In vivo varenicline does not alter ICSS thresholds; however, varenicline does block nicotine-induced facilitation of ICSS in rats (Vann et al., 2011). In many drug discrimination studies, including those in mice (Cunningham and McMahon, 2013), rats (Rollema et al., 2007; Jutkiewicz et al., 2011), and monkeys (Cunningham et al., 2012; Moerke et al., 2017) discriminating nicotine, varenicline fully substitutes for the nicotine discriminative stimulus, although additional studies in rats found this was only the case at relatively short pretreatment times (i.e., 5–40 minutes), whereas longer pretreatment times (i.e., 2–4 hours) resulted in very low levels of generalization with the nicotine discriminative stimulus (Le Foll et al., 2012). Under conditions in which varenicline only partially substitutes for the nicotine discriminative stimulus, varenicline sometimes, but not always, antagonizes the discriminative-stimulus effects of nicotine (LeSage et al., 2009; Cunningham and McMahon, 2013). When varenicline fully substituted for the nicotine discriminative stimulus in monkeys, combinations of nicotine and varenicline were synergistic (Cunningham et al., 2012). These observations, including full substitution of varenicline for nicotine, do not exclude the possibility that varenicline has lower efficacy than nicotine. Instead, it may simply be that for the training doses of nicotine studied in these discrimination assays, the efficacy demand might be sufficiently low, such that even a low-efficacy agonist can mimic the effects of a higher-efficacy agonist. Another possibility is that varenicline pretreatment results in acute tolerance through desensitization of the receptors where nicotine is acting to produce discriminative-stimulus effects; experimentally, acute cross-tolerance from varenicline to nicotine would not readily be distinguishable from antagonism of nicotine. These results are summarized in Table 1.

Although classified as a partial agonist at α4β2* nAChRs, as described above, varenicline has also been characterized as a full agonist at homomeric α7 nAChRs (Mihalak et al., 2006). In mice, varenicline dose-dependently blocks a conditioned place preference for nicotine (Bagdas et al., 2018a). Interestingly, α5 but not α7 nAChR knockout mice display an attenuation of varenicline’s effects on nicotine conditioned place preference (Bagdas et al., 2018a). That is, although varenicline is classified as an α7 nAChR full agonist, varenicline’s actions at this receptor in vivo seem somewhat dispensable. Meanwhile, it appears that nAChRs containing the α5 subunit may mediate at least some of varenicline’s effects.

Early reports of the side effects of varenicline prompted the FDA to require a black box warning for depression, suicidal thoughts, and suicidal actions on varenicline in 2009. However, several meta-analyses have found no evidence for an increase in any adverse neuropsychiatric events beyond sleep disturbances, which have been well-documented, and the warning has since been removed (Harrison-Woolrych and Ashton, 2011; Thomas et al., 2015). Other side effects, predominantly nausea, are reported more frequently than similar side effects with nicotine replacement therapies (Cahill et al., 2013, 2016). In addition to being generally unpleasant, side effects can also compromise compliance as well as promote relapse (Williams et al., 2007; Faessel et al., 2009; Kasliwal et al., 2009; Harrison-Woolrych and Ashton, 2011; Jimenez-Ruiz et al., 2013). Varenicline appears to approximately double one’s chances of remaining abstinent for a year over placebo alone (Gonzales et al., 2006), but it does not appear to be any more or less effective than multiple nicotine replacement therapies used in combination (Cahill et al., 2013, 2016; Baker et al., 2016).

C. Bupropion (Zyban)

Bupropion was approved for use in the United States as an antidepressant under the trade name Wellbutrin as early as 1985 but not as a pharmacotherapy for smoking cessation until 1997 (Zyban). In some countries, such as the United Kingdom, its only approved indication is as a smoking-cessation aid. It is considered an atypical antidepressant in the sense that it does not appear to function as a selective serotonin reuptake inhibitor, as is the case for many commonly prescribed antidepressants. Chemically, it is a substituted cathinone with a complex mechanism of action that is not completely understood. Thus, the exact mechanism(s) by which bupropion functions as a smoking-cessation aid is unknown, as it has effects at many targets in the central nervous system.

Bupropion shares many of its effects with other psychostimulants, and it is typically characterized as a dual norepinephrine and dopamine reuptake inhibitor (Stahl et al., 2004). In drug discrimination studies, both amphetamine, a structurally related compound, and cocaine, a structurally distinct compound, fully crossgeneralize with bupropion in both rats and monkeys (Jones et al., 1980; Blitzer and Becker, 1985; Kamien and Woolverton, 1989; Kleven et al., 1990; Lamb and Griffiths, 1990; Terry and Katz, 1997; Bondarev et al., 2003). Furthermore, bupropion supports self-administration behavior in rats as well as monkeys (Bergman et al., 1989; Lamb and Griffiths, 1990; Tella et al., 1997). This does not appear to completely translate to humans, however, as human studies have shown that although bupropion produces some subjective effects similar to abused drugs like amphetamine, it does not have abuse liability different from placebo (Griffith et al., 1983; Miller and Griffith, 1983).

Other data from studies comparing bupropion and nicotine have also produced mixed results. For example, in animals trained to discriminate nicotine, the ability of bupropion to substitute for nicotine has varied widely between studies. In rhesus monkeys, bupropion did not substitute for nicotine (Cunningham et al., 2012), and in mice, it only partially substituted for nicotine (Damaj et al., 2010); however, in rats, bupropion fully substituted (Wiley et al., 2002; Young and Glennon, 2002), partially substituted (Desai et al., 2003), or did not substitute (Shoaib et al., 2003), depending on the study. These results are summarized in Table 1.

Understanding the mechanism that underlies the therapeutic effects of bupropion for smoking cessation is further complicated by other actions of bupropion itself in addition to its active metabolites at a variety of central nervous system targets. One possibility is that bupropion functions as a smoking-cessation aid through antagonism of nAChRs (Slemmer et al., 2000). However, as bupropion is predominately metabolized by the CYP2B6 enzyme into its active metabolites R,R-hydroxybupropion, S,S-hydroxybupropion, threo-hydrobupropion, and erythro-hydrobupropion, these metabolites may also play an important role in its therapeutic effects (Cooper et al., 1984). Preclinical studies in mice found that both R,R-hydroxybupropion and S,S-hydroxybupropion were similar to bupropion in reversal of antagonist-precipitated nicotine withdrawal symptoms (Damaj et al., 2010), and the clinical effectiveness of bupropion treatment has also been linked to its active metabolites (Zhu et al., 2012). Clinical trials suggest that although bupropion is not as effective for smoking cessation as varenicline, it does work better than placebo (Hughes et al., 2014; Anthenelli et al., 2016; Stead et al., 2016; Windle et al., 2016). It is, however, a potent inhibitor of the CYP2D6 enzyme (Güzey et al., 2002; Jefferson et al., 2005), which is necessary for the metabolism of a variety compounds; thus, it may have adverse effects in combination with other drugs that rely on this mechanism for their clearance.

D. Off-Label Pharmacotherapies for Smoking Cessation

Clonidine and nortriptyline are considered “second line” medications for smoking cessation. Although these drugs appear to be more effective than placebo at maintaining abstinence at 6 months, they are associated with an increased risk of adverse side effects as compared with “first line” pharmacotherapies (Cahill et al., 2013). Furthermore, relatively little preclinical research has addressed the potential mechanism of action that these pharmacotherapies use to produce therapeutic effects in tobacco use disorder. Clonidine attenuates footshock-induced reinstatement of nicotine-seeking behavior in rats self-administering nicotine (Zislis et al., 2007; Yamada and Bruijnzeel, 2011) but, to our knowledge, has not been tested with nicotine in drug discrimination. Nortriptyline has no effect on nicotine discrimination and is only effective in decreasing nicotine self-administration in rats at doses sufficiently high to also depress responding for food (Wing and Shoaib, 2012). Mecamylamine, the nAChR antagonist, was originally approved for use in hypertension but has also been used both alone and in combination with nicotine as a potential therapy for tobacco use disorder. Alone, mecamylamine is ineffective for smoking cessation (Lancaster and Stead, 2000), but there is very limited evidence that it might be slightly more effective in combination with nicotine replacement therapy than nicotine replacement therapy alone (Rose et al., 1998). More recently, ENDS have been proposed for use in smoking cessation, as previously discussed. There is still a lack of evidence, but ENDS technologies might also help improve outcomes for smoking cessation, although the extent to which ENDS might be more effective than currently approved pharmacotherapies is unknown (Malas et al., 2016).

VI. Experimental Pharmacotherapies for Smoking Cessation

A. Allosteric Modulation of Nicotinic Acetylcholine Receptors

Allosteric modulation has long been recognized as the primary mechanism of action for FDA-approved drugs (e.g., benzodiazepines, barbiturates), but only more recently has it inspired widespread interest as an alternative strategy for targeting nAChRs, not just for smoking cessation but also for a variety of disorders characterized by dysfunction of the central nervous system. Allosteric interactions were originally proposed in the context of enzymatic reactions (Monod et al., 1965), but it was not long before this model was extended to include ligand binding at biologic membranes (e.g., nAChRs) (Changeux et al., 1967). Importantly, the word “allosteric” has been used somewhat ambiguously as a descriptor of ligands in the literature. For the sake of simplicity in the current review, we consider “orthosteric ligands” of nAChRs to include both acetylcholine and nicotine as well as other ligands that share the same canonical binding site as acetylcholine and nicotine; “allosteric ligands” will be used to refer to compounds that bind to nAChRs at sites that are distinct from the canonical “orthosteric” site. It has been theorized that one important feature of an allosteric modulator for use in smoking cessation might be that it does not produce effects alone in the absence of an orthosteric ligand. Instead, only when the orthosteric ligand is present would the allosteric modulator serve to produce a change in either the affinity and/or the efficacy of the orthosteric ligand (Uteshev, 2014) (Fig. 2). This is particularly promising in terms of a therapeutic strategy, as the effects of an allosteric modulator alone should be minimal, reducing the potential for unwanted side effects like those that often occur with approved substitution-type pharmacotherapies. For example, a negative allosteric modulator (NAM) might serve to reduce the reinforcing effects of nicotine, whereas a positive allosteric modulator (PAM) in combination with a more traditional orthosteric agonist therapy could reduce the dose of agonist required to produce a therapeutic effect. Decreasing the minimal effective therapeutic dose of an orthosteric ligand through combination with a positive allosteric ligand could both retain therapeutic effectiveness and decrease the potential for toxicity and other side effects, particularly when substitution pharmacotherapies are taken in larger quantities or more often than the recommended clinical indication. Furthermore, agonist activation of nAChRs also perpetuates cycles of activation and desensitization, which are also of importance in tobacco use disorder [see Picciotto et al. (2008) for review]. In this case, smaller doses of an orthosteric agonist in combination with a PAM should result in less receptor desensitization produced by the orthosteric ligand (Williams et al., 2011).

Fig. 2.
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Fig. 2.

Neuronal nAChR positive allosteric modulation. (Left) A neuronal nAChR with agonist bound at the orthosteric binding site allows for the influx of sodium and calcium into the cell. (Center) A positive allosteric modulator (PAM) bound to an allosteric site of a neuronal nAChR. By itself, it does not trigger the influx of ions into the cell. (Right) A neuronal nAChR PAM bound to an allosteric site, with an agonist at the orthosteric binding site, allows for an increased influx of sodium and calcium into the cell.

PAMs of nAChRs are proposed to increase the binding affinity and/or efficacy of an orthosteric agonist (Pandya and Yakel, 2013), whereas NAMs theoretically do the opposite by decreasing the binding affinity and/or efficacy of an orthosteric agonist. However, there are several different mechanisms by which allosteric modulators may accomplish these effects, which we will discuss briefly with a focus on heteromeric nAChRs. The prevailing consensus is that nAChRs are composed of dynamic proteins that are capable of multiple different states. However, for simplification, here we limit discussion to three possible states: closed, open, and desensitized. Furthermore, heteromeric nAChRs can potentially have 0, 1, or 2 agonist molecules bound. The likelihood of the receptor remaining stable in any one of the three possible states and the rates at which one state shifts to another state depend on the level of agonist occupancy (Changeux and Edelstein, 1998; Auerbach, 2010). At baseline equilibrium, when exogenous and endogenous signaling does not occur and no agonist is bound, nAChRs remain preferentially in the closed state. However, with an extremely low probability of shifting to the open state, the receptor may exist with some equilibrium between the closed state and the desensitized state (Williams et al., 2011). If a high concentration of agonist sufficient to saturate all the possible binding sites is rapidly applied, α4β2 nAChRs have an 80% probability of simultaneously shifting transiently into the open state before reaching a new equilibrium in the desensitized state (Li and Steinbach, 2010). Furthermore, it is known that once receptors are in the desensitized state, agonists bind with higher apparent affinity.

One way that a PAM of nAChRs may exert its effects would be to increase the agonist binding to the closed state of the receptor, which is experimentally represented by an increase in the potency of the agonist. This type of modulation might be most advantageous under a condition in which there is a low concentration of agonist, which would not otherwise produce a maximal response. By increasing the potency of the agonist, lower concentrations would be able to produce the maximum response. However, it would remain impossible to exceed the maximum response if the modulator is only changing the potency of the orthosteric ligand.

An alternative effect observed with PAMs is that they are often observed to increase the efficacy of an agonist. One way a PAM might accomplish this is via shifting the equilibrium between the open and closed states, making it easier to move from closed to open state. This would result in not only more receptors moving to the open state but also a greater likelihood that they might move from closed to open more than once before shifting to the desensitized state. Thus, this would yield a concurrent decrease in the rate of desensitization. Functionally, this could be observed as an overall increase in the time spent in the open state. Having this effect, a PAM can produce a transient increase in efficacy. The reverse of these conditions is hypothesized with the use of a NAM, leading to a transient decrease in agonist efficacy. However, neither a NAM nor a PAM in this scenario would alter how favored one state is over another, only the rate of change between states. Thus, receptors would eventually end up preferentially in the desensitized state, as under normal conditions.

Finally, if instead of altering the rate of change between states, as described above, a modulator functioned to shift equilibrium away from the desensitized state, this would result in yet another unique profile of observable effects. The result of this type of modulator would likely not be manifest as an increase in efficacy or the maximum effect, nor would it be observable under conditions in which the agonist interaction with the receptor pool is brief (e.g., acetylcholine broken down by acetylcholinesterase, rapid agonist application). Instead, it would be most apparent under equilibrium conditions, producing a significant amount of steady-state current (Williams et al., 2011).

The above is a simplified explanation of a theoretical model. Although there is experimental evidence that is consistent with these scenarios, it is not possible to prove or disprove them; they simply are not violated by what is currently known. Furthermore, it has been reported that, at least under some conditions, only a small percentage of available nAChRs are capable of being activated at once (McNerney et al., 2000; Li and Steinbach, 2010). Thus, the ability of a modulator to change receptors from the inactive to the active state is yet another possible mechanism by which it might enhance agonist activity. Finally, and perhaps most importantly, a similar but not identical model can be applied to homomeric nAChRs. Homomeric nAChRs are different from heteromeric nAChRs because they contain only one type of subunit; thus, they can potentially have 0, 1, 2, 3, 4, or 5 orthosteric agonist molecules bound to a single receptor (i.e., assemblies of five of the same subunit yield five essentially equal interfaces where ligand binding is possible). Heteromeric nAChRs, as described above, will have at the very most two similar interfaces for ligand binding, and it is likely that binding to one of these interfaces is not exactly interchangeable with binding to the other. Furthermore, an additional “fast” desensitization state has been described for homomeric α7 nAChRs, which is concentration-dependent and thought to be possible under conditions in which more agonist molecules are bound to a single receptor than is possible for heteromeric receptors (Papke et al., 2000). However, regardless of the exact mechanism, both negative and positive allosteric modulation of nAChRs represents an attractive therapeutic strategy that may circumvent the limitations inherent in targeting the canonical orthosteric site. A list of current nAChR NAMs and PAMs are shown in Tables 2 and 3, respectively, and are discussed below with regard to potential application for the treatment of tobacco use disorder.

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TABLE 2

Negative allosteric modulators of neuronal nAChRs and studies investigating them as pharmacotherapies for tobacco use disorder

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TABLE 3

Positive allosteric modulators of neuronal nAChRs and studies investigating them as pharmacotherapies for tobacco use disorder

1. Negative Allosteric Modulators

Allosteric modulators that selectively bind one or a subset of nAChR subtypes have been developed in vitro. The compound UCI-30002 is classified as a NAM at several nAChR subtypes. Specifically, in vitro work performed in transfected Xenopus oocytes demonstrated that this compound produces complete blockade of α7 and α3β4 subtypes but only partial blockade (approximately 80%) of the α4β2* subtype (Yoshimura et al., 2007). Further studies with this compound have demonstrated that it significantly diminishes nicotine self-administration in rats (Yoshimura et al., 2007). Other groups have discovered more selective nAChR NAMs, such as KAB-18, which has been characterized in vitro as a selective α4β2* nAChR NAM (Henderson et al., 2010). Additional studies suggest that the compounds DB04763, DB08122, and pefloxacin may act in vitro as α7 nAChR NAMs (Smelt et al., 2018). These nAChR NAMs are summarized in Table 2. However, more studies are needed to assess the selectivity of these compounds in vivo as well as their potential to be developed as pharmacotherapies for tobacco use disorder.

2. Positive Allosteric Modulators

a. α4β2* subtype selectivity

Desformylflustrabromine (dFBr) is classified both in vitro and in vivo as an α4β2* nAChR-selective PAM. It is a novel bromotryptamine derivative first isolated from Flustra foliacea, a marine bryozoan (Lysek et al., 2002; Peters et al., 2002), that was observed to selectively increase the current recorded in voltage clamp experiments conducted in oocytes transfected with human α4 and β2 nAChR subunits when coapplied with acetylcholine (Sala et al., 2005). Subsequently, it was successfully synthesized in the laboratory, where similar voltage clamp experiments in transfected oocytes reproduced the previous finding with the natural product dFBr; coapplication with acetylcholine increased ionic current through α4β2 nAChRs but not α7 nAChRs (Kim et al., 2007). Additionally, these experiments revealed a bell-shaped dose-response curve, with dFBr at concentrations in excess of 10 µM causing inhibition.

Further study of dFBr in vitro has increased our understanding of the possible mechanism(s) responsible for both its potentiating and inhibiting effects. In combination with different orthosteric nAChR agonists, dFBr increases the maximum effect of acetylcholine, nicotine, cytisine, and choline but does not change the potency of these agonists. Furthermore, dFBr increases the maximum effect of low efficacy agonists (i.e., cytisine, choline) more than it increases the maximum effect of high efficacy agonists (i.e., acetylcholine, nicotine). Additional experiments examined modulation by dFBr of the effects of three nAChR antagonists, DHβE, DMAB-anabaseine, and tropisetron, to determine if dFBr produced effects in the presence of the antagonist-bound receptor, but neither alone nor in combination with acetylcholine were any significant changes apparent with the addition of dFBr (Weltzin and Schulte, 2010). One interesting finding from these experiments was the ability of dFBr to reactivate desensitized receptors; that is, receptors in the desensitized state from previous saturating applications of acetylcholine did not respond to further addition of acetylcholine until dFBr was also applied to the preparation (Weltzin and Schulte, 2010). Altogether, these data suggest that the potentiating effect of dFBr can likely be attributed to an ability to change the equilibrium between receptor states (e.g., open) and that inhibition with higher concentrations of dFBr engages a different mechanism likely related to block of the ion channel (Weltzin and Schulte, 2010). Further voltage clamp experiments suggest that dFBr might have differential effects at α4β2* nAChRs dependent on the stoichiometry of the receptor (Weltzin et al., 2014). Other studies have found that dFBr also has inhibitory (but not potentiating) effects at muscle-type nAChRs, which also appears to be a result of dFBr binding within the ion channel, consistent with earlier studies suggesting that dFBr’s inhibitory effects were a result of channel blockade (Hamouda et al., 2015). Recent evidence from mutated receptors suggests that the magnitude of effect that dFBr produces may be dependent on the stoichiometry of the α4β2* nAChR in question (Weltzin and Schulte, 2015). However, the extent to which the details of the mechanism of dFBr observed in vitro are relevant in vivo is currently unknown. These findings are summarized in Table 3.

Desformylflustrabromine has also been studied extensively in vivo. In rats trained to self-administer nicotine (0.03 mg/kg per infusion), lower doses of dFBr (0.1 and 1 mg/kg) had no effect on nicotine self-administration, but larger doses (3 and 6 mg/kg) reduced the number of nicotine infusions earned (Liu, 2013). The largest dose of dFBr reduced the number of infusions earned by about half, from approximately 14 infusions under control conditions to seven infusions in combination with 6 mg/kg dFBr. Furthermore, in a separate group of rats, no dose of dFBr changed the number of responses made on either the active or inactive levers, indicating that there was not a general depression of behavior (Liu, 2013). To test the extent to which dFBr was acting via a central mechanism, cerebrospinal fluid was collected along with plasma after subcutaneous administration of dFBr. The elimination half-life of dFBr was estimated to be 8.6 hours, and it was present in the cerebrospinal fluid at about 30% of the concentration seen in plasma, indicating that it was crossing the blood-brain barrier and having actions in the central nervous system (Liu, 2013). Recently, in vivo studies with dFBr have demonstrated that this compound can reverse behavioral signs of nicotine withdrawal in nicotine-dependent mice (Hamouda et al., 2018). The effects of the nAChR PAM dFBr are summarized in Table 3.

Additional PAMs of α4β2* nAChRs have been identified. In vitro, the selective PAM NS9283 increased the potency of currents evoked with acetylcholine in human embryonic kidney 293 cells transfected with human α4β2 nAChR subunits. Furthermore, it was found that NS9283 did not alter the rate of desensitization of currents evoked with acetylcholine (Grupe et al., 2013). In the rat drug discrimination assay, NS9283 failed to produce substitution for 0.4 mg/kg nicotine at any dose tested (Mohler et al., 2014). When NS9283 was paired with doses of nicotine that did not produce significant substitution for 0.4 mg/kg nicotine, full substitution was observed. In the rat self-administration assay, NS9283 was not readily self-administered. However, both acute and repeated administration of NS9283 dose-dependently reduced nicotine self-administration in rats (Maurer et al., 2017). As α4β2* nAChRs are pentameric, it has been found that NS9283 selectively and preferentially acts on nAChRs with the combination of (3) α4 plus (2) β2 subunits (Timmermann et al., 2012; Grupe et al., 2013). This combination of subunits has been found to possess low sensitivity to acetylcholine (i.e., EC50 = 100 µM) and is in contrast to the combination of (2) α4 plus (3) β2 subunit ratio, which has been found to have high sensitivity to acetylcholine (i.e., EC50 = 1 µM) (Nelson et al., 2003; Moroni et al., 2006).

The compound (3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrrazol-4-yl)isoxazole) (CMPI) is structurally distinct from NS9283 and is also classified in vitro as a selective and preferential PAM at (3) α4 (2) β2 nAChRs (Albrecht et al., 2008; Hamouda et al., 2016). Interestingly, it appears that different binding sites on α4β2* nAChRs may be responsible for the actions of CMPI compared with NS9283 (Wang et al., 2017).

LY 2087101 is classified in vitro as a PAM at α4β2*, α4β4, and α7 nAChRs (Broad et al., 2006). Additionally, in vitro LY 2087101 produces an increase in both potency and magnitude of nicotine-induced currents (Broad et al., 2006). In vivo, this compound fails to produce substitution for 1 mg/kg nicotine at any dose tested in the mouse drug discrimination assay, even at doses that produce significant reduction of schedule-controlled responding (Moerke et al., 2016). Furthermore, when LY 2087101 is paired with doses of nicotine that do not produce significant substitution for 1 mg/kg nicotine, no potentiation is observed (Moerke et al., 2016). Thus, there appears to be a disconnect between the in vitro and in vivo literature regarding whether LY 2087101 is a true functional nAChR PAM. This discussion of α4β2* nAChR PAMs is summarized in Table 3.

b. α7 subtype selectivity

The α7 nAChR has garnered a lot of interest in its potential as a target for numerous cognitive diseases, including schizophrenia, Alzheimer disease, and inflammation-driven diseases, as well as smoking cessation. Because of the homomeric structure of the α7 nAChR, two distinctive types of PAMs have been developed to selectively leverage the pharmacology of this receptor. Specifically, type I PAMs increase the cholinergic activation of α7 nAChRs without altering either the receptor’s spatiotemporal features of synaptic transmission or the receptor’s desensitization kinetics, whereas type II α7 nAChR PAMs not only increase the duration of the open state of the receptor, leading to greater ion influx, but also decrease the time a receptor spends in a desensitized state. For further review of the mechanisms of the two distinctive types of α7 nAChR PAMs, please see the work of King et al. (2018).

NS1738 is a type I α7 nAChR PAM. In vitro, NS1738 has been found to neither displace nor alter radioligand binding to the nicotinic receptor agonist binding sites and did not produce a functional current at nAChRs. However, when NS1738 was combined with subthreshold doses of acetylcholine, a significant increase in peak currents in oocytes transfected with α7 nAChRs was observed. NS1738 was determined to be a type I PAM, as the compound produced no significant change in the desensitization kinetics of α7 nAChRs (Timmermann et al., 2007). More recent studies have examined the theoretical binding of NS1738 at α7 nAChRs, with a computer model examining the molecular docking, molecular dynamics stimulation, and free energy calculation. In this study, it was found that NS1738 has three theoretical binding sites (Kuang et al., 2016). In a mouse in vivo study, this compound successfully blocked somatic behavioral signs of antagonist-precipitated nicotine withdrawal (Jackson et al., 2018). However, NS1738 did not block increased anxiety-related behaviors in the same mice (Jackson et al., 2018). Meanwhile, in the same study, the α7 nAChR orthosteric agonist PNU282986 significantly reduced both the somatic signs and anxiety-related behavior associated with antagonist-precipitated nicotine withdrawal. Given wide interest in the α7 nAChR as a therapeutic target, other type I α7 nAChRs PAMs, such as the compound [N-(4-chlorophenyl)]-α-[(4-chlorophenyl)-aminomethylene]-3-methyl-5-isoxazoleacetamide (CCMI, also known as Compound 6) (Ng et al., 2007), and AVL-3288 (Bortz et al., 2016; Gee et al., 2017), have been developed but have not been investigated for their utility as pharmacotherapies in smoking cessation.

As opposed to the abovementioned type I PAM, type II α7 nAChR PAMs both increase the duration of the open state of the receptor and decrease the time a receptor spends in a desensitized state. PNU-120596 was first discovered via a high-throughput screen and has been characterized in vitro as a type II α7 nAChR PAM (Hurst et al., 2005; Barron et al., 2009). In mice, PNU-120596 enhanced the hypothermic effects of nicotine (Moerke et al., 2016). In a different study, this compound blocked some of the behavioral effects associated with nicotine withdrawal in mice (Jackson et al., 2018). However, PNU-120596 did not block increased anxiety-related behaviors in the same mice (Jackson et al., 2018). Additionally, PNU-120596 did not increase the substitution of subthreshold doses of nicotine to the discriminative stimulus of 1 mg/kg nicotine in the mouse drug discrimination assay (Moerke et al., 2016). Other type II α7 nAChR PAMs, such as the compound 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS) (Grønlien et al., 2007; Thomsen and Mikkelsen, 2012), A-867744 (Faghih et al., 2009), TBS-345, TBS-346, TBS-516, TBS-546, and TBS-556 (Chatzidaki et al., 2015), have been developed but have not been investigated for their utility in preclinical models typically used for evaluating potential pharmacotherapies for tobacco use disorder.

The in vivo effects of other α7 nAChR PAMs have been examined. Specifically, RO5126946 acts selectively as a PAM at human α7 nAChRs, as it was found to increase acetylcholine-induced currents and postpone current decay (Sahdeo et al., 2014). However, the application of RO5126946 did not alter receptor desensitization kinetics. In vivo, this compound increased the effects of nicotine in a rat footshock model of memory (Sahdeo et al., 2014), demonstrating potential as a cognitive enhancer.

In addition to type I and type II α7 nAChR PAMs, another class of α7 nAChR compounds are dual orthosteric agonists and PAMs, also known as ago-PAMs. GAT107 is the enantiomer of 4BP-TQS, derived from the parent compound TQS described above, and acts as both an orthosteric agonist and PAM at α7 nAChRs (Thakur et al., 2013; Papke et al., 2014). This dual effect allows GAT107 to produce a long-lasting activation of the α7 nAChR (Papke et al., 2018), which is likely a critical mediator in its in vivo anti-inflammatory and antipathologic pain effects (Bagdas et al., 2016). Additionally, the compound B-973 has been characterized in vitro as a functional ago-PAM at α7 nAChRs (Post-Munson et al., 2017). However, it remains to be seen if RO5126946, GAT107, or B-973 have potential relevance as smoking-cessation pharmacotherapies. Meanwhile, the compound JNJ-39393406, classified as an α7 nAChR PAM, was recently investigated in humans as a possible smoking-cessation pharmacotherapy. Prior to human trials, Johnson & Johnson stated that this compound produced positive outcomes in preclinical (i.e., rat and mouse) studies typically used to test for cognitive impairment seen in schizophrenia (Winterer et al., 2013). However, it is notable that Johnson & Johnson did not report examining JNJ-39393406 in combination with nicotine in preclinical animal models that are commonly used to evaluate potential pharmacotherapies for tobacco use disorder. It was reported that this compound failed to reduce cigarette craving or total smoking and did not increase number of quit days in study participants. Furthermore, this compound did not meet study criteria, and Johnson & Johnson reported that they would not be moving forward with the development of this compound as a smoking-cessation pharmacotherapy (Perkins et al., 2018). The above-discussed α7 nAChR PAMs are summarized in Table 3.

Current pharmacotherapies associated with the best outcomes for smoking cessation (i.e., nicotinic agonists) are active at all subtypes of nAChR, albeit with differing affinities for the various receptor subtypes. Although it appears that α4β2* nAChRs are important targets for smoking-cessation therapeutics based on preclinical data, the contribution of other nAChRs should not be discounted. Thus, using a more selective positive allosteric modulator could provide several advantages from a therapeutic standpoint. Greater selectivity, to the extent that only one receptor subtype mediates all effects targeted for smoking cessation, allows for less side effects resulting from actions at other receptor subtypes. Conversely, it may be that a polypharmacological approach (i.e., targeting multiple receptors or signaling pathways) may be the most advantageous approach for the development of new pharmacological treatments for smoking cessation. That relapse is relatively common even among individuals receiving nicotine replacement therapies (which are arguably the most effective pharmacotherapies currently available) may be one indication that polypharmacological approaches are a strategy worth pursuing.

B. Acetylcholinesterase Inhibitors

Identifying novel targets for smoking cessation and developing drugs that produce a desirable profile of action at these targets is a process that can take more than 10 years and an investment of several billion dollars before a new drug ever reaches the market. One way to circumvent this process is to consider repurposing drugs that have already been approved by the FDA and examining their potential to produce therapeutic effects outside of their current indications.

Acetylcholinesterase (AChE) inhibitors represent one such class of drugs, as three are currently approved by the FDA for the treatment of cognitive deficits associated with Alzheimer disease: donepezil, rivastigmine, and galantamine. AChE inhibitors produce their effects by preventing AChE, an endogenous enzyme that helps regulate cholinergic neurotransmission, from breaking down acetylcholine. In theory, this would lead to increases in receptor activation by endogenous acetylcholine and might produce nicotine-like effects. Early experiments that attempted to use this strategy in rats found that the nicotine discriminative stimulus could not be mimicked or potentiated by the AChE inhibitor physostigmine (Rosecrans and Meltzer, 1981; Pratt et al., 1983). However, when physostigmine was trained as a discriminative stimulus, although nicotine did not substitute, oxotremorine and arecoline, both mAChR agonists, did (Jung et al., 1988). Thus, AChE inhibitors were not studied further as potential treatments for smoking cessation.

Following FDA approval for Alzheimer disease, however, a small study of patients undergoing treatment of alcohol dependence indicated that galantamine was effective in reducing smoking in this population (Diehl et al., 2006), renewing interest in AChE inhibitors as pharmacotherapies for smoking cessation. Discrimination studies in rats (Giarola et al., 2011) and monkeys (Moerke and McMahon, 2019) provided evidence that donepezil and galantamine partially substituted for the nicotine discriminative stimulus, and several groups found that both donepezil and galantamine were effective at reducing nicotine self-administration in rats (Hopkins et al., 2012; Liu, 2013; Kimmey et al., 2014; Ashare et al., 2016). Results from preclinical studies using self-administration and drug discrimination assays are summarized in Table 1.

All three FDA-approved AChE inhibitors have been examined in smokers, and thus far galantamine has shown the most potential for smoking cessation. Rivastigmine, like galantamine, reduced tobacco consumption in alcohol-dependent individuals (Diehl et al., 2009) but had no effect on cigarette smoking in methamphetamine-dependent individuals (De la Garza and Yoon, 2011). Furthermore, donepezil did not effectively decrease cigarette smoking in a pilot study (Ashare et al., 2012). In comparison, only one clinical study using galantamine found no decrease in smoking among individuals with schizophrenia (Kelly et al., 2008). Several other clinical studies have shown that galantamine can attenuate cigarette craving and reduce smoking satisfaction in addition to reducing overall tobacco consumption (Sofuoglu et al., 2012; Ashare et al., 2016; MacLean et al., 2018).

One point of interest is that of the three AChE inhibitors approved for Alzheimer disease and discussed here, only galantamine has been shown to also have activity as a positive allosteric modulator of nAChRs (Maelicke et al., 2001; Farlow, 2003). However, recent studies suggest that galantamine does not functionally act at human α4β2* or α7 nAChRs as a PAM (Kowal et al., 2018). Thus, although it seems unlikely that action as a PAM is responsible for the relative success of galantamine to decrease smoking in some populations, it cannot be ruled out entirely. Clearly, much more work needs to be done both to evaluate AChE inhibitors in general as potential smoking-cessation pharmacotherapies as well as to determine if galantamine offers any benefits in comparison with existing pharmacotherapies for smoking cessation.

C. Psilocybin

Psychedelics, including psilocybin, were actively studied for their potential in treating substance use disorders from the 1950s into the early 1970s. Passage of the Controlled Substances Act in 1970, however, which classified psilocybin as a Schedule I compound, effectively halted any further development as a pharmacotherapy for decades.

Psilocybin is a prodrug that in vivo is rapidly metabolized to psilocin, an agonist at serotonin (5HT) receptors, and there is overwhelming evidence to support that 5HT2A is the most important 5HT receptor subtype for mediating the effects of classic psychedelics [see Nichols (2016) for review]. Recent study of psilocybin in the preclinical literature, however, suggests that 5HT2A receptors are only partially responsible for mediating the discriminative stimulus effects of psilocybin; in rats trained to discriminate 0.5 mg/kg psilocybin, M100907, a 5HT2A receptor antagonist, did not fully antagonize the discriminative stimulus effects of psilocybin up to doses that suppressed responding (Winter et al., 2007). In humans, however, there is abundant evidence that 5HT2A receptors mediate the subjective effects of psilocybin (Vollenweider et al., 1998; Kometer et al., 2012, 2013; Quednow et al., 2012).

A recent pilot study administered psilocybin over the course of a 15-week program of cognitive behavior therapy for current smokers. Participants received either two or three administrations of psilocybin under guided supervision in the treatment setting, and 12 of the 15 (80%) participants were confirmed abstinent by measure of urine cotinine levels at a 6-month follow-up; this is a notably higher percentage than is typically seen for smoking interventions, which is generally less than 35% (Johnson et al., 2014). Furthermore, follow-up at 2.5 years revealed that 60% of the participants had remained abstinent (Johnson et al., 2017). Such positive results should be interpreted with caution given the small sample size of the study and the fact that there was no comparison group; nonetheless, further trials are underway with psilocybin for not only tobacco use disorder but also alcohol use disorder, cocaine use disorder, depression, anorexia, and obsessive-compulsive disorder.

D. Hypocretin Receptor Antagonists

Hypocretins (Hcrt), also referred to as orexins, are neuropeptides produced within a small population of neurons located in the hypothalamus with projections to many other regions of the brain, including the limbic system (Peyron et al., 1998). Two G-protein coupled receptors, hcrtR1 and hcrtR2, have been identified, and the hypocretin system plays an important role in the homeostatic regulation of adaptive behaviors associated with arousal. Hypocretin signaling is necessary for the regulation of sleep cycles (Nishino et al., 2000; Thannickal et al., 2000) in addition to playing an important role in feeding (Haynes et al., 2000; Inutsuka et al., 2014) and mating (Muschamp et al., 2007) behaviors. Furthermore, hypocretin has also been implicated in behaviors of overconsumption, including substance use disorders (Barson and Leibowitz, 2017). For a current review on hypocretin receptors, please see Wang et al. (2018).

Accumulating preclinical evidence focuses on hypocretin receptor antagonists in reducing the reinforcing effects of nicotine. For example, both the hcrtR1 antagonist SB-334867 as well as a dual hcrtR1/hcrtR2 antagonist, almorexant, dose-dependently reduced nicotine self-administration in rats (Hollander et al., 2008; LeSage et al., 2010). However, 2-SORA, a hcrtR2 selective antagonist, had no effect on nicotine self-administration in rats, suggesting hcrtR1-mediated activity was responsible for decreases in self-administration (Uslaner et al., 2014). In tests of nicotine reinstatement, on the other hand, both hcrtR1 and hcrtR2 have been implicated but different groups have reported results that make interpretation difficult. Specifically, one group has reported attenuation of cue-induced reinstatement of nicotine-seeking behavior with hcrtR1 antagonist SB-334867 but not hcrtR2 antagonist TCSOX229 (Plaza-Zabala et al., 2013), whereas a second group has reported that cue-induced reinstatement of nicotine-seeking behavior is blocked by hcrtR2 antagonist 2-SORA (Uslaner et al., 2014), and a third group has reported no effect on cue-induced reinstatement of nicotine-seeking behavior with dual hcrtR1/hcrtR2 antagonist TCS1102 (Khoo et al., 2017). Furthermore, SB-334867 did not block footshock-induced reinstatement of nicotine seeking (Plaza-Zabala et al., 2010), and 2-SORA did not block nicotine-induced reinstatement of nicotine-seeking behavior (Uslaner et al., 2014). Results from preclinical studies of hcrtR compounds in nicotine self-administration and nicotine discrimination assays are summarized in Table 1. Nonetheless, a clinical trial is currently planned to evaluate the effects of suvorexant, a dual hcrtR1/hcrtR2 antagonist currently approved for the treatment of insomnia, in treatment of tobacco use disorder.

VII. Conclusion

A major challenge in the development of pharmacotherapies for tobacco use disorder lies in the apparent probability that several different nAChR subtypes play important roles in the behavioral effects of nicotine. Furthermore, these receptor subtypes can be dynamically regulated by nicotine and other nAChR ligands through both orthosteric and allosteric action, which adds to the complexity of designing therapeutic interventions, including options with limited side effects. In the case of varenicline, it appears that polypharmacology at nAChR subtypes, with some differences from nicotine, including lower efficacy at some subtypes, is important for the compound’s mechanisms of action. However, the limited therapeutic utility of varenicline, albeit at least equal to nicotine replacement, leaves room for improvement. Thus, in developing the next generation of pharmacotherapies for tobacco use disorder, it may be critical to design compounds that interact with more than one nAChR subtype and/or other receptor systems. Additionally, the pharmacokinetics of potential smoking-cessation pharmacotherapies, including a suitable long duration of action and bioavailability through the oral, nasal, and inhalation roues, are critical in ongoing development strategies. Most of the experimental compounds listed in the second half of this review were administered preclinically via a systemic injection, leaving other routes of administration unexplored thus far. We hope to have highlighted here the untapped therapeutic potential of nAChR allosteric modulators as smoking-cessation aids, which is a relatively new area of drug discovery. It may be that varying the route of administration may enhance the therapeutic window of a compound developed as a medication for smoking cessation. For example, one intriguing development in the battle against tobacco use disorder is ENDS. Work on the delivery of compounds in vapor form has only just begun, and there are other intriguing formulations and routes, including nasal mist. Although 55 years have passed since the first Surgeon General’s report on tobacco in 1964, which officially linked lung cancer to cigarette smoking (U.S. Department of Health, Education, and Welfare, 1964), there is still much work to be done in the development of pharmacotherapies to treat tobacco use disorder.

Acknowledgments

The authors would like to acknowledge and thank Dr. Imad Damaj for his invaluable advice and insights.

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Moerke, McMahon, Wilkerson.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01 DA25267 and UG3 DA48353].

  • https://doi.org/10.1124/pr.119.018028.

Abbreviations

AChE
acetylcholinesterase
CCMI
[N-(4-chlorophenyl)]-α-[(4-chlorophenyl)-aminomethylene]-3-methyl-5-isoxazoleacetamide
CMPI
(3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrrazol-4-yl)isoxazole)
dFBr
desformylflustrabromine
DHβE
dihydro-β-erythroidine
ENDS
electronic nicotine delivery system
FDA
Food and Drug Administration
hcrt
hypocretin
5HT
serotonin
ICSS
intracranial self-stimulation
mAChR
muscarinic acetylcholine receptor
MLA
methyllycaconitine
nAChR
nicotinic acetylcholine receptor
NAM
negative allosteric modulator
PAM
positive allosteric modulator
TQS
3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3Hcyclopentan[c]quinoline-8-sulfonamide
WHO
World Health Organization
  • U.S. Government work not protected by U.S. copyright

References

  1. ↵
    1. Albrecht BK,
    2. Berry V,
    3. Boezio AA,
    4. Cao L,
    5. Clarkin K,
    6. Guo W,
    7. Harmange JC,
    8. Hierl M,
    9. Huang L,
    10. Janosky B, et al.
    (2008) Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators. Bioorg Med Chem Lett 18:5209–5212.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Albuquerque EX,
    2. Pereira EF,
    3. Castro NG,
    4. Alkondon M,
    5. Reinhardt S,
    6. Schröder H, and
    7. Maelicke A
    (1995) Nicotinic receptor function in the mammalian central nervous system. Ann N Y Acad Sci 757:48–72.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Alkondon M,
    2. Pereira EF,
    3. Wonnacott S, and
    4. Albuquerque EX
    (1992) Blockade of nicotinic currents in hippocampal neurons defines methyllycaconitine as a potent and specific receptor antagonist. Mol Pharmacol 41:802–808.
    OpenUrlAbstract
  4. ↵
    1. Alsharari SD,
    2. Freitas K, and
    3. Damaj MI
    (2013) Functional role of alpha7 nicotinic receptor in chronic neuropathic and inflammatory pain: studies in transgenic mice. Biochem Pharmacol 86:1201–1207.
    OpenUrlCrossRefPubMed
  5. ↵
    1. American Psychiatric Association
    (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th ed, American Psychiatric Association, Arlington, VA.
  6. ↵
    1. Anand R,
    2. Conroy WG,
    3. Schoepfer R,
    4. Whiting P, and
    5. Lindstrom J
    (1991) Neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes have a pentameric quaternary structure. J Biol Chem 266:11192–11198.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Anderson DJ,
    2. Malysz J,
    3. Grønlien JH,
    4. El Kouhen R,
    5. Håkerud M,
    6. Wetterstrand C,
    7. Briggs CA, and
    8. Gopalakrishnan M
    (2009) Stimulation of dopamine release by nicotinic acetylcholine receptor ligands in rat brain slices correlates with the profile of high, but not low, sensitivity alpha4beta2 subunit combination. Biochem Pharmacol 78:844–851.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Ando K and
    2. Yanagita T
    (1981) Cigarette smoking in rhesus monkeys. Psychopharmacology (Berl) 72:117–127.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Andreasen JT,
    2. Olsen GM,
    3. Wiborg O, and
    4. Redrobe JP
    (2009) Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests. J Psychopharmacol 23:797–804.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Anthenelli RM,
    2. Benowitz NL,
    3. West R,
    4. St Aubin L,
    5. McRae T,
    6. Lawrence D,
    7. Ascher J,
    8. Russ C,
    9. Krishen A, and
    10. Evins AE
    (2016) Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet 387:2507–2520.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Armitage AK,
    2. Dollery CT,
    3. George CF,
    4. Houseman TH,
    5. Lewis PJ, and
    6. Turner DM
    (1975) Absorption and metabolism of nicotine from cigarettes. BMJ 4:313–316.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Ashare RL,
    2. Kimmey BA,
    3. Rupprecht LE,
    4. Bowers ME,
    5. Hayes MR, and
    6. Schmidt HD
    (2016) Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers. Transl Psychiatry 6:e713.
    OpenUrl
  13. ↵
    1. Ashare RL,
    2. Ray R,
    3. Lerman C, and
    4. Strasser AA
    (2012) Cognitive effects of the acetylcholinesterase inhibitor, donepezil, in healthy, non-treatment seeking smokers: a pilot feasibility study. Drug Alcohol Depend 126:263–267.
    OpenUrlPubMed
  14. ↵
    1. Auerbach A
    (2010) The gating isomerization of neuromuscular acetylcholine receptors. J Physiol 588:573–586.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Babb S,
    2. Malarcher A,
    3. Schauer G,
    4. Asman K, and
    5. Jamal A
    (2017) Quitting smoking among adults - United States, 2000-2015. MMWR Morb Mortal Wkly Rep 65:1457–1464.
    OpenUrlPubMed
  16. ↵
    1. Bagdas D,
    2. Alkhlaif Y,
    3. Jackson A,
    4. Carroll FI,
    5. Ditre JW, and
    6. Damaj MI
    (2018a) New insights on the effects of varenicline on nicotine reward, withdrawal and hyperalgesia in mice. Neuropharmacology 138:72–79.
    OpenUrl
  17. ↵
    1. Bagdas D,
    2. Diester CM,
    3. Riley J,
    4. Carper M,
    5. Alkhlaif Y,
    6. AlOmari D,
    7. Alayoubi H,
    8. Poklis JL, and
    9. Damaj MI
    (2019) Assessing nicotine dependence using an oral nicotine free-choice paradigm in mice. Neuropharmacology 157:107669.
    OpenUrl
  18. ↵
    1. Bagdas D,
    2. Gurun MS,
    3. Flood P,
    4. Papke RL, and
    5. Damaj MI
    (2018b) New insights on neuronal nicotinic acetylcholine receptors as targets for pain and inflammation: a focus on α7 nAChRs. Curr Neuropharmacol 16:415–425.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Bagdas D,
    2. Wilkerson JL,
    3. Kulkarni A,
    4. Toma W,
    5. AlSharari S,
    6. Gul Z,
    7. Lichtman AH,
    8. Papke RL,
    9. Thakur GA, and
    10. Damaj MI
    (2016) The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain. Br J Pharmacol 173:2506–2520.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Baker TB,
    2. Piper ME,
    3. Stein JH,
    4. Smith SS,
    5. Bolt DM,
    6. Fraser DL, and
    7. Fiore MC
    (2016) Effects of nicotine patch vs varenicline vs combination nicotine replacement therapy on smoking cessation at 26 weeks: a randomized clinical trial. JAMA 315:371–379.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Balfour DJ
    (1994) Neural mechanisms underlying nicotine dependence. Addiction 89:1419–1423.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Banks ML and
    2. Negus SS
    (2017) Insights from preclinical choice models on treating drug addiction. Trends Pharmacol Sci 38:181–194.
    OpenUrl
  23. ↵
    1. Barron SC,
    2. McLaughlin JT,
    3. See JA,
    4. Richards VL, and
    5. Rosenberg RL
    (2009) An allosteric modulator of alpha7 nicotinic receptors, N-(5-Chloro-2,4-dimethoxyphenyl)-N′-(5-methyl-3-isoxazolyl)-urea (PNU-120596), causes conformational changes in the extracellular ligand binding domain similar to those caused by acetylcholine. Mol Pharmacol 76:253–263.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Barson JR and
    2. Leibowitz SF
    (2017) Orexin/hypocretin system: role in food and drug overconsumption. Int Rev Neurobiol 136:199–237.
    OpenUrl
  25. ↵
    1. Bauco P and
    2. Wise RA
    (1994) Potentiation of lateral hypothalamic and midline mesencephalic brain stimulation reinforcement by nicotine: examination of repeated treatment. J Pharmacol Exp Ther 271:294–301.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Bauer CT,
    2. Banks ML,
    3. Blough BE, and
    4. Negus SS
    (2013) Use of intracranial self-stimulation to evaluate abuse-related and abuse-limiting effects of monoamine releasers in rats. Br J Pharmacol 168:850–862.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Benowitz NL
    (1990) Clinical pharmacology of inhaled drugs of abuse: implications in understanding nicotine dependence. NIDA Res Monogr 99:12–29.
    OpenUrlPubMed
  28. ↵
    1. Benowitz NL
    (1996) Pharmacology of nicotine: addiction and therapeutics. Annu Rev Pharmacol Toxicol 36:597–613.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Benowitz NL
    (2008) Neurobiology of nicotine addiction: implications for smoking cessation treatment. Am J Med 121 (4 Suppl 1):S3–S10.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Benowitz NL and
    2. Henningfield JE
    (1994) Establishing a nicotine threshold for addiction. The implications for tobacco regulation. N Engl J Med 331:123–125.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Benowitz NL,
    2. Hukkanen J, and
    3. Jacob P III.
    (2009) Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol 29–60.
  32. ↵
    1. Benowitz NL and
    2. Jacob P III.
    (1993) Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers. Clin Pharmacol Ther 53:316–323.
    OpenUrlCrossRefPubMed
  33. ↵
    1. Benowitz NL and
    2. Jacob P III.
    (1994) Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 56:483–493.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Benowitz NL and
    2. Jacob P III.
    (2001) Trans-3′-hydroxycotinine: disposition kinetics, effects and plasma levels during cigarette smoking. Br J Clin Pharmacol 51:53–59.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Benowitz NL,
    2. Jacob P III.,
    3. Olsson P, and
    4. Johansson CL
    (1992) Intravenous nicotine retards transdermal absorption of nicotine: evidence of blood flow--limited percutaneous absorption. Clin Pharmacol Ther 52:223–230.
    OpenUrlPubMed
  36. ↵
    1. Benowitz NL,
    2. Jacob P III., and
    3. Perez-Stable E
    (1996) CYP2D6 phenotype and the metabolism of nicotine and cotinine. Pharmacogenetics 6:239–242.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Benowitz NL,
    2. Lessov-Schlaggar CN,
    3. Swan GE, and
    4. Jacob P III.
    (2006) Female sex and oral contraceptive use accelerate nicotine metabolism. Clin Pharmacol Ther 79:480–488.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Benowitz NL,
    2. Pomerleau OF,
    3. Pomerleau CS, and
    4. Jacob P III.
    (2003) Nicotine metabolite ratio as a predictor of cigarette consumption. Nicotine Tob Res 5:621–624.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Benwell ME,
    2. Balfour DJ, and
    3. Anderson JM
    (1988) Evidence that tobacco smoking increases the density of (-)-[3H]nicotine binding sites in human brain. J Neurochem 50:1243–1247.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Bergman J,
    2. Madras BK,
    3. Johnson SE, and
    4. Spealman RD
    (1989) Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys. J Pharmacol Exp Ther 251:150–155.
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Bertrand D and
    2. Terry AV Jr..
    (2018) The wonderland of neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 151:214–225.
    OpenUrl
  42. ↵
    1. Besheer J,
    2. Palmatier MI,
    3. Metschke DM, and
    4. Bevins RA
    (2004) Nicotine as a signal for the presence or absence of sucrose reward: a Pavlovian drug appetitive conditioning preparation in rats. Psychopharmacology (Berl) 172:108–117.
    OpenUrlCrossRefPubMed
  43. ↵
    1. Bespalov A,
    2. Lebedev A,
    3. Panchenko G, and
    4. Zvartau E
    (1999) Effects of abused drugs on thresholds and breaking points of intracranial self-stimulation in rats. Eur Neuropsychopharmacol 9:377–383.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Besson M,
    2. David V,
    3. Suarez S,
    4. Cormier A,
    5. Cazala P,
    6. Changeux JP, and
    7. Granon S
    (2006) Genetic dissociation of two behaviors associated with nicotine addiction: beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome. Psychopharmacology (Berl) 187:189–199.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Besson M,
    2. Guiducci S,
    3. Granon S,
    4. Guilloux JP,
    5. Guiard B,
    6. Repérant C,
    7. Faure P,
    8. Pons S,
    9. Cannazza G,
    10. Zoli M, et al.
    (2016) Alterations in alpha5* nicotinic acetylcholine receptors result in midbrain- and hippocampus-dependent behavioural and neural impairments. Psychopharmacology (Berl) 233:3297–3314.
    OpenUrlCrossRefPubMed
  46. ↵
    1. Bevins RA and
    2. Palmatier MI
    (2004) Extending the role of associative learning processes in nicotine addiction. Behav Cogn Neurosci Rev 3:143–158.
    OpenUrlCrossRefPubMed
  47. ↵
    1. Biala G,
    2. Staniak N, and
    3. Budzynska B
    (2010) Effects of varenicline and mecamylamine on the acquisition, expression, and reinstatement of nicotine-conditioned place preference by drug priming in rats. Naunyn Schmiedebergs Arch Pharmacol 381:361–370.
    OpenUrlCrossRefPubMed
  48. ↵
    1. Bierut LJ,
    2. Stitzel JA,
    3. Wang JC,
    4. Hinrichs AL,
    5. Grucza RA,
    6. Xuei X,
    7. Saccone NL,
    8. Saccone SF,
    9. Bertelsen S,
    10. Fox L, et al.
    (2008) Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165:1163–1171.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Bisaga A,
    2. Padilla M,
    3. Garawi F,
    4. Sullivan MA, and
    5. Haney M
    (2007) Effects of alternative reinforcer and craving on the choice to smoke cigarettes in the laboratory. Hum Psychopharmacol 22:41–47.
    OpenUrlCrossRefPubMed
  50. ↵
    1. Blitzer RD and
    2. Becker RE
    (1985) Characterization of the bupropion cue in the rat: lack of evidence for a dopaminergic mechanism. Psychopharmacology (Berl) 85:173–177.
    OpenUrlPubMed
  51. ↵
    1. Bonano JS,
    2. Glennon RA,
    3. De Felice LJ,
    4. Banks ML, and
    5. Negus SS
    (2014) Abuse-related and abuse-limiting effects of methcathinone and the synthetic “bath salts” cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats. Psychopharmacology (Berl) 231:199–207.
    OpenUrlCrossRef
  52. ↵
    1. Bondarev ML,
    2. Bondareva TS,
    3. Young R, and
    4. Glennon RA
    (2003) Behavioral and biochemical investigations of bupropion metabolites. Eur J Pharmacol 474:85–93.
    OpenUrlCrossRefPubMed
  53. ↵
    1. Bortz DM,
    2. Upton BA,
    3. Mikkelsen JD, and
    4. Bruno JP
    (2016) Positive allosteric modulators of the α7 nicotinic acetylcholine receptor potentiate glutamate release in the prefrontal cortex of freely-moving rats. Neuropharmacology 111:78–91.
    OpenUrl
  54. ↵
    1. Breese CR,
    2. Marks MJ,
    3. Logel J,
    4. Adams CE,
    5. Sullivan B,
    6. Collins AC, and
    7. Leonard S
    (1997) Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282:7–13.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Brioni JD,
    2. Kim DJ, and
    3. O’Neill AB
    (1996) Nicotine cue: lack of effect of the alpha 7 nicotinic receptor antagonist methyllycaconitine. Eur J Pharmacol 301:1–5.
    OpenUrlCrossRefPubMed
  56. ↵
    1. Broad LM,
    2. Zwart R,
    3. Pearson KH,
    4. Lee M,
    5. Wallace L,
    6. McPhie GI,
    7. Emkey R,
    8. Hollinshead SP,
    9. Dell CP,
    10. Baker SR, et al.
    (2006) Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J Pharmacol Exp Ther 318:1108–1117.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Brown RW,
    2. Collins AC,
    3. Lindstrom JM, and
    4. Whiteaker P
    (2007) Nicotinic alpha5 subunit deletion locally reduces high-affinity agonist activation without altering nicotinic receptor numbers. J Neurochem 103:204–215.
    OpenUrlPubMed
  58. ↵
    1. Bruijnzeel AW and
    2. Gold MS
    (2005) The role of corticotropin-releasing factor-like peptides in cannabis, nicotine, and alcohol dependence. Brain Res Brain Res Rev 49:505–528.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Bruijnzeel AW,
    2. Zislis G,
    3. Wilson C, and
    4. Gold MS
    (2007) Antagonism of CRF receptors prevents the deficit in brain reward function associated with precipitated nicotine withdrawal in rats. Neuropsychopharmacology 32:955–963.
    OpenUrlCrossRefPubMed
  60. ↵
    1. Brunzell DH,
    2. Boschen KE,
    3. Hendrick ES,
    4. Beardsley PM, and
    5. McIntosh JM
    (2010) Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors in the nucleus accumbens shell regulate progressive ratio responding maintained by nicotine. Neuropsychopharmacology 35:665–673.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Cahill K,
    2. Lindson-Hawley N,
    3. Thomas KH,
    4. Fanshawe TR, and
    5. Lancaster T
    (2016) Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 5:CD006103.
    OpenUrlPubMed
  62. ↵
    1. Cahill K,
    2. Stevens S, and
    3. Lancaster T
    (2014) Pharmacological treatments for smoking cessation. JAMA 311:193–194.
    OpenUrlCrossRefPubMed
  63. ↵
    1. Cahill K,
    2. Stevens S,
    3. Perera R, and
    4. Lancaster T
    (2013) Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 5:CD009329.
    OpenUrlCrossRefPubMed
  64. ↵
    1. Cairns NJ and
    2. Wonnacott S
    (1988) [3H](-)nicotine binding sites in fetal human brain. Brain Res 475:1–7.
    OpenUrlCrossRefPubMed
  65. ↵
    1. Caponnetto P,
    2. Campagna D,
    3. Cibella F,
    4. Morjaria JB,
    5. Caruso M,
    6. Russo C, and
    7. Polosa R
    (2013) EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as tobacco cigarettes substitute: a prospective 12-month randomized control design study. PLoS One 8:e66317.
    OpenUrlCrossRefPubMed
  66. ↵
    1. Carlezon WA Jr.. and
    2. Chartoff EH
    (2007) Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Protoc 2:2987–2995.
    OpenUrlCrossRefPubMed
  67. ↵
    1. Cassidy RN,
    2. Tidey JW,
    3. Kahler CW,
    4. Wray TB, and
    5. Colby SM
    (2015) Increasing the value of an alternative monetary reinforcer reduces cigarette choice in adolescents. Nicotine Tob Res 17:1449–1455.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Chaiton M,
    2. Diemert L,
    3. Cohen JE,
    4. Bondy SJ,
    5. Selby P,
    6. Philipneri A, and
    7. Schwartz R
    (2016) Estimating the number of quit attempts it takes to quit smoking successfully in a longitudinal cohort of smokers. BMJ Open 6:e011045.
    OpenUrlAbstract/FREE Full Text
  69. ↵
    1. Changeux JP and
    2. Edelstein SJ
    (1998) Allosteric receptors after 30 years. Neuron 21:959–980.
    OpenUrlCrossRefPubMed
  70. ↵
    1. Changeux JP,
    2. Thiéry J,
    3. Tung Y, and
    4. Kittel C
    (1967) On the cooperativity of biological membranes. Proc Natl Acad Sci USA 57:335–341.
    OpenUrlFREE Full Text
  71. ↵
    1. Chatzidaki A,
    2. D’Oyley JM,
    3. Gill-Thind JK,
    4. Sheppard TD, and
    5. Millar NS
    (2015) The influence of allosteric modulators and transmembrane mutations on desensitisation and activation of α7 nicotinic acetylcholine receptors. Neuropharmacology 97:75–85.
    OpenUrl
  72. ↵
    1. Clarke PB and
    2. Kumar R
    (1983a) Characterization of the locomotor stimulant action of nicotine in tolerant rats. Br J Pharmacol 80:587–594.
    OpenUrlPubMed
  73. ↵
    1. Clarke PB and
    2. Kumar R
    (1983b) The effects of nicotine on locomotor activity in non-tolerant and tolerant rats. Br J Pharmacol 78:329–337.
    OpenUrlCrossRefPubMed
  74. ↵
    1. Coe JW,
    2. Brooks PR,
    3. Vetelino MG,
    4. Wirtz MC,
    5. Arnold EP,
    6. Huang J,
    7. Sands SB,
    8. Davis TI,
    9. Lebel LA,
    10. Fox CB, et al.
    (2005) Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 48:3474–3477.
    OpenUrlCrossRefPubMed
  75. ↵
    1. Cohen A,
    2. Koob GF, and
    3. George O
    (2012) Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence. Neuropsychopharmacology 37:2153–2160.
    OpenUrlCrossRefPubMed
  76. ↵
    1. Collins RJ,
    2. Weeks JR,
    3. Cooper MM,
    4. Good PI, and
    5. Russell RR
    (1984) Prediction of abuse liability of drugs using IV self-administration by rats. Psychopharmacology (Berl) 82:6–13.
    OpenUrlCrossRefPubMed
  77. ↵
    1. Cooper E,
    2. Couturier S, and
    3. Ballivet M
    (1991) Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor. Nature 350:235–238.
    OpenUrlCrossRefPubMed
  78. ↵
    1. Cooper TB,
    2. Suckow RF, and
    3. Glassman A
    (1984) Determination of bupropion and its major basic metabolites in plasma by liquid chromatography with dual-wavelength ultraviolet detection. J Pharm Sci 73:1104–1107.
    OpenUrlCrossRefPubMed
  79. ↵
    1. Corne SJ and
    2. Edge ND
    (1958) Pharmacological properties of pempidine (1:2:2:6:6-pentamethylpiperidine), a new ganglion-blocking compound. Br J Pharmacol Chemother 13:339–349.
    OpenUrlPubMed
  80. ↵
    1. Corrigall WA and
    2. Coen KM
    (1989) Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl) 99:473–478.
    OpenUrlCrossRefPubMed
  81. ↵
    1. Corrigall WA,
    2. Franklin KB,
    3. Coen KM, and
    4. Clarke PB
    (1992) The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology (Berl) 107:285–289.
    OpenUrlCrossRefPubMed
  82. ↵
    1. Court JA,
    2. Lloyd S,
    3. Thomas N,
    4. Piggott MA,
    5. Marshall EF,
    6. Morris CM,
    7. Lamb H,
    8. Perry RH,
    9. Johnson M, and
    10. Perry EK
    (1998) Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use. Neuroscience 87:63–78.
    OpenUrlCrossRefPubMed
  83. ↵
    1. Creese I and
    2. Sibley DR
    (1981) Receptor adaptations to centrally acting drugs. Annu Rev Pharmacol Toxicol 21:357–391.
    OpenUrlCrossRefPubMed
  84. ↵
    1. Cunningham CS,
    2. Javors MA, and
    3. McMahon LR
    (2012) Pharmacologic characterization of a nicotine-discriminative stimulus in rhesus monkeys. J Pharmacol Exp Ther 341:840–849.
    OpenUrlAbstract/FREE Full Text
  85. ↵
    1. Cunningham CS and
    2. McMahon LR
    (2013) Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids. Psychopharmacology (Berl) 228:321–333.
    OpenUrlCrossRefPubMed
  86. ↵
    1. Cunningham CS,
    2. Moerke MJ,
    3. Javors MA,
    4. Carroll FI, and
    5. McMahon LR
    (2016) Attenuated nicotine-like effects of varenicline but not other nicotinic ACh receptor agonists in monkeys receiving nicotine daily. Br J Pharmacol 173:3454–3466.
    OpenUrl
  87. ↵
    1. Cunningham CS,
    2. Moerke MJ, and
    3. McMahon LR
    (2014) The discriminative stimulus effects of mecamylamine in nicotine-treated and untreated rhesus monkeys. Behav Pharmacol 25:296–305.
    OpenUrl
  88. ↵
    1. Cunningham CS,
    2. Moerke MJ, and
    3. McMahon LR
    (2019) Discriminative stimulus effects of mecamylamine and nicotine in rhesus monkeys: central and peripheral mechanisms. Pharmacol Biochem Behav 179:27–33.
    OpenUrl
  89. ↵
    1. Dale LC,
    2. Hurt RD,
    3. Offord KP,
    4. Lawson GM,
    5. Croghan IT, and
    6. Schroeder DR
    (1995) High-dose nicotine patch therapy. Percentage of replacement and smoking cessation. JAMA 274:1353–1358.
    OpenUrlCrossRefPubMed
  90. ↵
    1. Damaj MI,
    2. Grabus SD,
    3. Navarro HA,
    4. Vann RE,
    5. Warner JA,
    6. King LS,
    7. Wiley JL,
    8. Blough BE,
    9. Lukas RJ, and
    10. Carroll FI
    (2010) Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice. J Pharmacol Exp Ther 334:1087–1095.
    OpenUrlAbstract/FREE Full Text
  91. ↵
    1. Dani JA and
    2. Bertrand D
    (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47:699–729.
    OpenUrlCrossRefPubMed
  92. ↵
    1. Dani JA and
    2. De Biasi M
    (2001) Cellular mechanisms of nicotine addiction. Pharmacol Biochem Behav 70:439–446.
    OpenUrlCrossRefPubMed
  93. ↵
    1. De Biasi M and
    2. Salas R
    (2008) Influence of neuronal nicotinic receptors over nicotine addiction and withdrawal. Exp Biol Med (Maywood) 233:917–929.
    OpenUrlCrossRefPubMed
  94. ↵
    1. De la Garza R II. and
    2. Yoon JH
    (2011) Evaluation of the effects of rivastigmine on cigarette smoking by methamphetamine-dependent volunteers. Prog Neuropsychopharmacol Biol Psychiatry 35:1827–1830.
    OpenUrlPubMed
  95. ↵
    1. de Moura FB and
    2. McMahon LR
    (2017) The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice. Psychopharmacology (Berl) 234:781–792.
    OpenUrl
  96. ↵
    1. Dempsey D,
    2. Tutka P,
    3. Jacob P III.,
    4. Allen F,
    5. Schoedel K,
    6. Tyndale RF, and
    7. Benowitz NL
    (2004) Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther 76:64–72.
    OpenUrlCrossRefPubMed
  97. ↵
    1. Deneau G and
    2. Inoki R
    (1967) Nicotine self-administration in monkeys. Ann N Y Acad Sci 142:277–279.
    OpenUrlCrossRef
  98. ↵
    1. Desai RI,
    2. Barber DJ, and
    3. Terry P
    (1999) Asymmetric generalization between the discriminative stimulus effects of nicotine and cocaine. Behav Pharmacol 10:647–656.
    OpenUrlPubMed
  99. ↵
    1. Desai RI,
    2. Barber DJ, and
    3. Terry P
    (2003) Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats. Psychopharmacology (Berl) 167:335–343.
    OpenUrlPubMed
  100. ↵
    1. Diehl A,
    2. Nakovics H,
    3. Croissant B,
    4. Smolka MN,
    5. Batra A, and
    6. Mann K
    (2006) Galantamine reduces smoking in alcohol-dependent patients: a randomized, placebo-controlled trial. Int J Clin Pharmacol Ther 44:614–622.
    OpenUrlPubMed
  101. ↵
    1. Diehl A,
    2. Nakovics H,
    3. Mutschler J,
    4. Hermann D, and
    5. Kiefer F
    (2009) Rivastigmine reduces tobacco craving in alcohol-dependent smokers. Pharmacopsychiatry 42:89–94.
    OpenUrl
  102. ↵
    1. Donny EC,
    2. Caggiula AR,
    3. Knopf S, and
    4. Brown C
    (1995) Nicotine self-administration in rats. Psychopharmacology (Berl) 122:390–394.
    OpenUrlCrossRefPubMed
  103. ↵
    1. Donny EC,
    2. Caggiula AR,
    3. Mielke MM,
    4. Booth S,
    5. Gharib MA,
    6. Hoffman A,
    7. Maldovan V,
    8. Shupenko C, and
    9. McCallum SE
    (1999) Nicotine self-administration in rats on a progressive ratio schedule of reinforcement. Psychopharmacology (Berl) 147:135–142.
    OpenUrlCrossRefPubMed
  104. ↵
    1. Donny EC,
    2. Denlinger RL,
    3. Tidey JW,
    4. Koopmeiners JS,
    5. Benowitz NL,
    6. Vandrey RG,
    7. al’Absi M,
    8. Carmella SG,
    9. Cinciripini PM,
    10. Dermody SS, et al.
    (2015) Randomized trial of reduced-nicotine standards for cigarettes. N Engl J Med 373:1340–1349.
    OpenUrlCrossRefPubMed
  105. ↵
    1. Donovick PJ,
    2. Burright RG, and
    3. Zuromski E
    (1970) Localization of quinine aversion within the septum, habenula, and interpeduncular nucleus of the rat. J Comp Physiol Psychol 71:376–383.
    OpenUrlCrossRefPubMed
  106. ↵
    1. Dwoskin LP,
    2. Smith AM,
    3. Wooters TE,
    4. Zhang Z,
    5. Crooks PA, and
    6. Bardo MT
    (2009) Nicotinic receptor-based therapeutics and candidates for smoking cessation. Biochem Pharmacol 78:732–743.
    OpenUrlCrossRefPubMed
  107. ↵
    1. Egea J,
    2. Buendia I,
    3. Parada E,
    4. Navarro E,
    5. León R, and
    6. Lopez MG
    (2015) Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochem Pharmacol 97:463–472.
    OpenUrlCrossRefPubMed
  108. ↵
    1. Eglen RM
    (2005) Muscarinic receptor subtype pharmacology and physiology. Prog Med Chem 43:105–136.
    OpenUrlCrossRefPubMed
  109. ↵
    1. Epping-Jordan MP,
    2. Watkins SS,
    3. Koob GF, and
    4. Markou A
    (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76–79.
    OpenUrlCrossRefPubMed
  110. ↵
    1. Etter JF and
    2. Bullen C
    (2011) Saliva cotinine levels in users of electronic cigarettes. Eur Respir J 38:1219–1220.
    OpenUrlFREE Full Text
  111. ↵
    1. Eugster CH,
    2. Müller GF, and
    3. Good R
    (1965) [The active ingredients from Amanita muscaria: ibotenic acid and muscazone]. Tetrahedron Lett 23:1813–1815.
    OpenUrl
  112. ↵
    1. Exley R,
    2. McIntosh JM,
    3. Marks MJ,
    4. Maskos U, and
    5. Cragg SJ
    (2012) Striatal α5 nicotinic receptor subunit regulates dopamine transmission in dorsal striatum. J Neurosci 32:2352–2356.
    OpenUrlAbstract/FREE Full Text
  113. ↵
    1. Faessel H,
    2. Ravva P, and
    3. Williams K
    (2009) Pharmacokinetics, safety, and tolerability of varenicline in healthy adolescent smokers: a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 31:177–189.
    OpenUrlCrossRefPubMed
  114. ↵
    1. Faghih R,
    2. Gopalakrishnan SM,
    3. Gronlien JH,
    4. Malysz J,
    5. Briggs CA,
    6. Wetterstrand C,
    7. Ween H,
    8. Curtis MP,
    9. Sarris KA,
    10. Gfesser GA, et al.
    (2009) Discovery of 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor. J Med Chem 52:3377–3384.
    OpenUrlCrossRefPubMed
  115. ↵
    1. Fant RV,
    2. Schuh KJ, and
    3. Stitzer ML
    (1995) Response to smoking as a function of prior smoking amounts. Psychopharmacology (Berl) 119:385–390.
    OpenUrlPubMed
  116. ↵
    1. Farlow MR
    (2003) Clinical pharmacokinetics of galantamine. Clin Pharmacokinet 42:1383–1392.
    OpenUrlCrossRefPubMed
  117. ↵
    1. Farsalinos KE,
    2. Romagna G,
    3. Tsiapras D,
    4. Kyrzopoulos S, and
    5. Voudris V
    (2013) Evaluating nicotine levels selection and patterns of electronic cigarette use in a group of “vapers” who had achieved complete substitution of smoking. Subst Abuse 7:139–146.
    OpenUrlPubMed
  118. ↵
    1. Farsalinos KE,
    2. Spyrou A,
    3. Tsimopoulou K,
    4. Stefopoulos C,
    5. Romagna G, and
    6. Voudris V
    (2014) Nicotine absorption from electronic cigarette use: comparison between first and new-generation devices. Sci Rep 4:4133.
    OpenUrlCrossRefPubMed
  119. ↵
    1. Fenster CP,
    2. Whitworth TL,
    3. Sheffield EB,
    4. Quick MW, and
    5. Lester RA
    (1999) Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine. J Neurosci 19:4804–4814.
    OpenUrlAbstract/FREE Full Text
  120. ↵
    1. Flores CM,
    2. Dávila-García MI,
    3. Ulrich YM, and
    4. Kellar KJ
    (1997) Differential regulation of neuronal nicotinic receptor binding sites following chronic nicotine administration. J Neurochem 69:2216–2219.
    OpenUrlPubMed
  121. ↵
    1. Fowler CD,
    2. Lu Q,
    3. Johnson PM,
    4. Marks MJ, and
    5. Kenny PJ
    (2011) Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature 471:597–601.
    OpenUrlCrossRefPubMed
  122. ↵
    1. Fowler CD,
    2. Tuesta L, and
    3. Kenny PJ
    (2013) Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice. Psychopharmacology (Berl), doi: 10.1007/s00213-013-3235-1 [published ahead of print].
    OpenUrlCrossRef
  123. ↵
    1. Fredriksson R,
    2. Lagerström MC,
    3. Lundin LG, and
    4. Schiöth HB
    (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272.
    OpenUrlAbstract/FREE Full Text
  124. ↵
    1. Freitas K,
    2. Carroll FI, and
    3. Negus SS
    (2016) Comparison of effects produced by nicotine and the α4β2-selective agonist 5-I-A-85380 on intracranial self-stimulation in rats. Exp Clin Psychopharmacol 24:65–75.
    OpenUrl
  125. ↵
    1. Freitas KC,
    2. Carroll FI, and
    3. Negus SS
    (2015) Effects of nicotinic acetylcholine receptor agonists in assays of acute pain-stimulated and pain-depressed behaviors in rats. J Pharmacol Exp Ther 355:341–350.
    OpenUrlAbstract/FREE Full Text
  126. ↵
    1. Fudala PJ,
    2. Teoh KW, and
    3. Iwamoto ET
    (1985) Pharmacologic characterization of nicotine-induced conditioned place preference. Pharmacol Biochem Behav 22:237–241.
    OpenUrlCrossRefPubMed
  127. ↵
    1. Gamaleddin I,
    2. Guranda M,
    3. Scherma M,
    4. Fratta W,
    5. Makriyannis A,
    6. Vadivel SK,
    7. Goldberg SR, and
    8. Le Foll B
    (2013) AM404 attenuates reinstatement of nicotine seeking induced by nicotine-associated cues and nicotine priming but does not affect nicotine- and food-taking. J Psychopharmacol 27:564–571.
    OpenUrlCrossRefPubMed
  128. ↵
    1. Garcha HS and
    2. Stolerman IP
    (1993) Discriminative stimulus effects of the nicotine antagonist mecamylamine in rats. J Psychopharmacol 7 (1 Suppl):43–51.
    OpenUrlCrossRefPubMed
  129. ↵
    1. Garcia KL,
    2. Lê AD, and
    3. Tyndale RF
    (2014) Effect of food training and training dose on nicotine self-administration in rats. Behav Brain Res 274:10–18.
    OpenUrl
  130. ↵
    1. GBD 2017 Risk Factor Collaborators
    (2018) Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392:1923–1994.
    OpenUrlCrossRefPubMed
  131. ↵
    1. Gee KW,
    2. Olincy A,
    3. Kanner R,
    4. Johnson L,
    5. Hogenkamp D,
    6. Harris J,
    7. Tran M,
    8. Edmonds SA,
    9. Sauer W,
    10. Yoshimura R, et al.
    (2017) First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288. J Psychopharmacol 31:434–441.
    OpenUrl
  132. ↵
    1. George O,
    2. Ghozland S,
    3. Azar MR,
    4. Cottone P,
    5. Zorrilla EP,
    6. Parsons LH,
    7. O’Dell LE,
    8. Richardson HN, and
    9. Koob GF
    (2007) CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proc Natl Acad Sci USA 104:17198–17203.
    OpenUrlAbstract/FREE Full Text
  133. ↵
    1. George O,
    2. Grieder TE,
    3. Cole M, and
    4. Koob GF
    (2010) Exposure to chronic intermittent nicotine vapor induces nicotine dependence. Pharmacol Biochem Behav 96:104–107.
    OpenUrlCrossRefPubMed
  134. ↵
    1. George O,
    2. Lloyd A,
    3. Carroll FI,
    4. Damaj MI, and
    5. Koob GF
    (2011) Varenicline blocks nicotine intake in rats with extended access to nicotine self-administration. Psychopharmacology (Berl) 213:715–722.
    OpenUrlCrossRefPubMed
  135. ↵
    1. Giarola A,
    2. Auber A, and
    3. Chiamulera C
    (2011) Acetylcholinesterase inhibitors partially generalize to nicotine discriminative stimulus effect in rats. Behav Pharmacol 22:1–6.
    OpenUrlPubMed
  136. ↵
    1. Gilpin NW,
    2. Whitaker AM,
    3. Baynes B,
    4. Abdel AY,
    5. Weil MT, and
    6. George O
    (2014) Nicotine vapor inhalation escalates nicotine self-administration. Addict Biol 19:587–592.
    OpenUrlCrossRefPubMed
  137. ↵
    1. Goldberg SR,
    2. Spealman RD, and
    3. Goldberg DM
    (1981) Persistent behavior at high rates maintained by intravenous self-administration of nicotine. Science 214:573–575.
    OpenUrlAbstract/FREE Full Text
  138. ↵
    1. Gommans J,
    2. Stolerman IP, and
    3. Shoaib M
    (2000) Antagonism of the discriminative and aversive stimulus properties of nicotine in C57BL/6J mice. Neuropharmacology 39:2840–2847.
    OpenUrlCrossRefPubMed
  139. ↵
    1. Gonzales D,
    2. Rennard SI,
    3. Nides M,
    4. Oncken C,
    5. Azoulay S,
    6. Billing CB,
    7. Watsky EJ,
    8. Gong J,
    9. Williams KE,
    10. Reeves KR, and Varenicline Phase 3 Study Group
    (2006) Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 296:47–55.
    OpenUrlCrossRefPubMed
  140. ↵
    1. Goodwin AK,
    2. Hiranita T, and
    3. Paule MG
    (2015) The reinforcing effects of nicotine in humans and nonhuman primates: a review of intravenous self-administration evidence and future directions for research. Nicotine Tob Res 17:1297–1310.
    OpenUrlCrossRefPubMed
  141. ↵
    1. Gotti C and
    2. Clementi F
    (2004) Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74:363–396.
    OpenUrlCrossRefPubMed
  142. ↵
    1. Gotti C,
    2. Guiducci S,
    3. Tedesco V,
    4. Corbioli S,
    5. Zanetti L,
    6. Moretti M,
    7. Zanardi A,
    8. Rimondini R,
    9. Mugnaini M,
    10. Clementi F, et al.
    (2010) Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2* receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement. J Neurosci 30:5311–5325.
    OpenUrlAbstract/FREE Full Text
  143. ↵
    1. Gourlay SG and
    2. Benowitz NL
    (1997) Arteriovenous differences in plasma concentration of nicotine and catecholamines and related cardiovascular effects after smoking, nicotine nasal spray, and intravenous nicotine. Clin Pharmacol Ther 62:453–463.
    OpenUrlCrossRefPubMed
  144. ↵
    1. Green RM and
    2. Lawyer SR
    (2014) Steeper delay and probability discounting of potentially real versus hypothetical cigarettes (but not money) among smokers. Behav Processes 108:50–56.
    OpenUrl
  145. ↵
    1. Griffith JD,
    2. Carranza J,
    3. Griffith C, and
    4. Miller LL
    (1983) Bupropion: clinical assay for amphetamine-like abuse potential. J Clin Psychiatry 44:206–208.
    OpenUrlPubMed
  146. ↵
    1. Griffiths R,
    2. Brady J, and
    3. Bradford L
    (1979) Predicting the abuse liability of drugs with animal drug self-administration procedures: psychomotor stimulants and hallucinogens. Adv Behav Pharmacol 2:163–208.
    OpenUrl
  147. ↵
    1. Grønlien JH,
    2. Håkerud M,
    3. Ween H,
    4. Thorin-Hagene K,
    5. Briggs CA,
    6. Gopalakrishnan M, and
    7. Malysz J
    (2007) Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol Pharmacol 72:715–724.
    OpenUrlAbstract/FREE Full Text
  148. ↵
    1. Grupe M,
    2. Jensen AA,
    3. Ahring PK,
    4. Christensen JK, and
    5. Grunnet M
    (2013) Unravelling the mechanism of action of NS9283, a positive allosteric modulator of (α4)3(β2)2 nicotinic ACh receptors. Br J Pharmacol 168:2000–2010.
    OpenUrlCrossRefPubMed
  149. ↵
    1. Güzey C,
    2. Norström A, and
    3. Spigset O
    (2002) Change from the CYP2D6 extensive metabolizer to the poor metabolizer phenotype during treatment with bupropion. Ther Drug Monit 24:436–437.
    OpenUrlCrossRefPubMed
  150. ↵
    1. Haikala H and
    2. Ahtee L
    (1988) Antagonism of the nicotine-induced changes of the striatal dopamine metabolism in mice by mecamylamine and pempidine. Naunyn Schmiedebergs Arch Pharmacol 338:169–173.
    OpenUrlPubMed
  151. ↵
    1. Hajek P,
    2. Jackson P, and
    3. Belcher M
    (1988) Long-term use of nicotine chewing gum. Occurrence, determinants, and effect on weight gain. JAMA 260:1593–1596.
    OpenUrlCrossRefPubMed
  152. ↵
    1. Hajek P,
    2. West R,
    3. Foulds J,
    4. Nilsson F,
    5. Burrows S, and
    6. Meadow A
    (1999) Randomized comparative trial of nicotine polacrilex, a transdermal patch, nasal spray, and an inhaler. Arch Intern Med 159:2033–2038.
    OpenUrlCrossRefPubMed
  153. ↵
    1. Hammond DK,
    2. Bjercke RJ,
    3. Langone JJ, and
    4. Strobel HW
    (1991) Metabolism of nicotine by rat liver cytochromes P-450. Assessment utilizing monoclonal antibodies to nicotine and cotinine. Drug Metab Dispos 19:804–808.
    OpenUrlAbstract
  154. ↵
    1. Hamouda AK,
    2. Deba F,
    3. Wang ZJ, and
    4. Cohen JB
    (2016) Photolabeling a nicotinic acetylcholine receptor (nAChR) with an (α4)3(β2)2 nAChR-selective positive allosteric modulator. Mol Pharmacol 89:575–584.
    OpenUrlAbstract/FREE Full Text
  155. ↵
    1. Hamouda AK,
    2. Jackson A,
    3. Bagdas D, and
    4. Imad Damaj M
    (2018) Reversal of nicotine withdrawal signs through positive allosteric modulation of α4β2 nicotinic acetylcholine receptors in male mice. Nicotine Tob Res 20:903–907.
    OpenUrl
  156. ↵
    1. Hamouda AK,
    2. Wang ZJ,
    3. Stewart DS,
    4. Jain AD,
    5. Glennon RA, and
    6. Cohen JB
    (2015) Desformylflustrabromine (dFBr) and [3H]dFBr-labeled binding sites in a nicotinic acetylcholine receptor. Mol Pharmacol 88:1–11.
    OpenUrlAbstract/FREE Full Text
  157. ↵
    1. Harkness PC and
    2. Millar NS
    (2002) Changes in conformation and subcellular distribution of alpha4beta2 nicotinic acetylcholine receptors revealed by chronic nicotine treatment and expression of subunit chimeras. J Neurosci 22:10172–10181.
    OpenUrlAbstract/FREE Full Text
  158. ↵
    1. Harrison-Woolrych M and
    2. Ashton J
    (2011) Psychiatric adverse events associated with varenicline: an intensive postmarketing prospective cohort study in New Zealand. Drug Saf 34:763–772.
    OpenUrlCrossRefPubMed
  159. ↵
    1. Hatchell PC and
    2. Collins AC
    (1977) Influences of genotype and sex on behavioral tolerance to nicotine in mice. Pharmacol Biochem Behav 6:25–30.
    OpenUrlCrossRefPubMed
  160. ↵
    1. Hatsukami DK,
    2. Kotlyar M,
    3. Hertsgaard LA,
    4. Zhang Y,
    5. Carmella SG,
    6. Jensen JA,
    7. Allen SS,
    8. Shields PG,
    9. Murphy SE,
    10. Stepanov I, et al.
    (2010) Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation. Addiction 105:343–355.
    OpenUrlCrossRefPubMed
  161. ↵
    1. Haynes AC,
    2. Jackson B,
    3. Chapman H,
    4. Tadayyon M,
    5. Johns A,
    6. Porter RA, and
    7. Arch JR
    (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 96:45–51.
    OpenUrlCrossRefPubMed
  162. ↵
    1. Hazell P,
    2. Peterson DW, and
    3. Laverty R
    (1978) Brief communication. Inability of hexamethonium to block the discriminative stimulus (SD) property of nicotine. Pharmacol Biochem Behav 9:137–140.
    OpenUrlPubMed
  163. ↵
    1. Hecht SS,
    2. Hochalter JB,
    3. Villalta PW, and
    4. Murphy SE
    (2000) 2′-Hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: formation of a lung carcinogen precursor. Proc Natl Acad Sci USA 97:12493–12497.
    OpenUrlAbstract/FREE Full Text
  164. ↵
    1. Henderson BJ,
    2. Pavlovicz RE,
    3. Allen JD,
    4. González-Cestari TF,
    5. Orac CM,
    6. Bonnell AB,
    7. Zhu MX,
    8. Boyd RT,
    9. Li C,
    10. Bergmeier SC, et al.
    (2010) Negative allosteric modulators that target human alpha4beta2 neuronal nicotinic receptors. J Pharmacol Exp Ther 334:761–774.
    OpenUrlAbstract/FREE Full Text
  165. ↵
    1. Henningfield JE and
    2. Goldberg SR
    (1983) Control of behavior by intravenous nicotine injections in human subjects. Pharmacol Biochem Behav 19:1021–1026.
    OpenUrlCrossRefPubMed
  166. ↵
    1. Henningfield JE and
    2. Keenan RM
    (1993) Nicotine delivery kinetics and abuse liability. J Consult Clin Psychol 61:743–750.
    OpenUrlCrossRefPubMed
  167. ↵
    1. Henningfield JE,
    2. Miyasato K, and
    3. Jasinski DR
    (1983) Cigarette smokers self-administer intravenous nicotine. Pharmacol Biochem Behav 19:887–890.
    OpenUrlCrossRefPubMed
  168. ↵
    1. Henningfield JE,
    2. Miyasato K, and
    3. Jasinski DR
    (1985) Abuse liability and pharmacodynamic characteristics of intravenous and inhaled nicotine. J Pharmacol Exp Ther 234:1–12.
    OpenUrlAbstract/FREE Full Text
  169. ↵
    1. Henningfield JE,
    2. Smith TT,
    3. Kleykamp BA,
    4. Fant RV, and
    5. Donny EC
    (2016) Nicotine self-administration research: the legacy of Steven R. Goldberg and implications for regulation, health policy, and research. Psychopharmacology (Berl) 233:3829–3848.
    OpenUrl
  170. ↵
    1. Hollander JA,
    2. Lu Q,
    3. Cameron MD,
    4. Kamenecka TM, and
    5. Kenny PJ
    (2008) Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci USA 105:19480–19485.
    OpenUrlAbstract/FREE Full Text
  171. ↵
    1. Hopkins TJ,
    2. Rupprecht LE,
    3. Hayes MR,
    4. Blendy JA, and
    5. Schmidt HD
    (2012) Galantamine, an acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, attenuates nicotine taking and seeking in rats. Neuropsychopharmacology 37:2310–2321.
    OpenUrlPubMed
  172. ↵
    1. Hubbard JE and
    2. Gohd RS
    (1975) Tolerance development to the arousal effects of nicotine. Pharmacol Biochem Behav 3:471–476.
    OpenUrlPubMed
  173. ↵
    1. Hughes JR
    (2006) Clinical significance of tobacco withdrawal. Nicotine Tob Res 8:153–156.
    OpenUrlCrossRefPubMed
  174. ↵
    1. Hughes JR
    (2007) Effects of abstinence from tobacco: valid symptoms and time course. Nicotine Tob Res 9:315–327.
    OpenUrlCrossRefPubMed
  175. ↵
    1. Hughes JR,
    2. Gust SW,
    3. Keenan R,
    4. Fenwick JW,
    5. Skoog K, and
    6. Higgins ST
    (1991) Long-term use of nicotine vs placebo gum. Arch Intern Med 151:1993–1998.
    OpenUrlCrossRefPubMed
  176. ↵
    1. Hughes JR,
    2. Keely J, and
    3. Naud S
    (2004) Shape of the relapse curve and long-term abstinence among untreated smokers. Addiction 99:29–38.
    OpenUrlCrossRefPubMed
  177. ↵
    1. Hughes JR,
    2. Stead LF,
    3. Hartmann-Boyce J,
    4. Cahill K, and
    5. Lancaster T
    (2014) Antidepressants for smoking cessation. Cochrane Database Syst Rev CD000031.
  178. ↵
    1. Hukkanen J,
    2. Jacob P III., and
    3. Benowitz NL
    (2005) Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57:79–115.
    OpenUrlAbstract/FREE Full Text
  179. ↵
    1. Hulme EC,
    2. Birdsall NJ, and
    3. Buckley NJ
    (1990) Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 30:633–673.
    OpenUrlCrossRefPubMed
  180. ↵
    1. Hurst RS,
    2. Hajós M,
    3. Raggenbass M,
    4. Wall TM,
    5. Higdon NR,
    6. Lawson JA,
    7. Rutherford-Root KL,
    8. Berkenpas MB,
    9. Hoffmann WE,
    10. Piotrowski DW, et al.
    (2005) A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization. J Neurosci 25:4396–4405.
    OpenUrlAbstract/FREE Full Text
  181. ↵
    1. Hurt RD,
    2. Dale LC,
    3. Croghan GA,
    4. Croghan IT,
    5. Gomez-Dahl LC, and
    6. Offord KP
    (1998) Nicotine nasal spray for smoking cessation: pattern of use, side effects, relief of withdrawal symptoms, and cotinine levels. Mayo Clin Proc 73:118–125.
    OpenUrlCrossRefPubMed
  182. ↵
    1. Hurt RD,
    2. Offord KP,
    3. Lauger GG,
    4. Marusić Z,
    5. Fagerström KO,
    6. Enright PL, and
    7. Scanlon PD
    (1995) Cessation of long-term nicotine gum use--a prospective, randomized trial. Addiction 90:407–413.
    OpenUrlCrossRefPubMed
  183. ↵
    1. Huston-Lyons D and
    2. Kornetsky C
    (1992) Effects of nicotine on the threshold for rewarding brain stimulation in rats. Pharmacol Biochem Behav 41:755–759.
    OpenUrlCrossRefPubMed
  184. ↵
    1. Huynh C,
    2. Fam J,
    3. Ahmed SH, and
    4. Clemens KJ
    (2017) Rats quit nicotine for a sweet reward following an extensive history of nicotine use. Addict Biol 22:142–151.
    OpenUrlCrossRef
  185. ↵
    1. Igari M,
    2. Alexander JC,
    3. Ji Y,
    4. Qi X,
    5. Papke RL, and
    6. Bruijnzeel AW
    (2014) Varenicline and cytisine diminish the dysphoric-like state associated with spontaneous nicotine withdrawal in rats. Neuropsychopharmacology 39:455–465.
    OpenUrlCrossRefPubMed
  186. ↵
    1. Ikemoto S,
    2. Qin M, and
    3. Liu ZH
    (2006) Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area. J Neurosci 26:723–730.
    OpenUrlAbstract/FREE Full Text
  187. ↵
    1. Inutsuka A,
    2. Inui A,
    3. Tabuchi S,
    4. Tsunematsu T,
    5. Lazarus M, and
    6. Yamanaka A
    (2014) Concurrent and robust regulation of feeding behaviors and metabolism by orexin neurons. Neuropharmacology 85:451–460.
    OpenUrlCrossRefPubMed
  188. ↵
    1. Jackson A,
    2. Papke RL, and
    3. Damaj MI
    (2018) Pharmacological modulation of the α7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal. Psychopharmacology (Berl) 235:1897–1905.
    OpenUrl
  189. ↵
    1. Jackson KJ,
    2. Marks MJ,
    3. Vann RE,
    4. Chen X,
    5. Gamage TF,
    6. Warner JA, and
    7. Damaj MI
    (2010) Role of alpha5 nicotinic acetylcholine receptors in pharmacological and behavioral effects of nicotine in mice. J Pharmacol Exp Ther 334:137–146.
    OpenUrlAbstract/FREE Full Text
  190. ↵
    1. Jackson KJ,
    2. McIntosh JM,
    3. Brunzell DH,
    4. Sanjakdar SS, and
    5. Damaj MI
    (2009) The role of alpha6-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal. J Pharmacol Exp Ther 331:547–554.
    OpenUrlAbstract/FREE Full Text
  191. ↵
    1. Jefferson JW,
    2. Pradko JF, and
    3. Muir KT
    (2005) Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Ther 27:1685–1695.
    OpenUrlCrossRefPubMed
  192. ↵
    1. Jenner P,
    2. Gorrod JW, and
    3. Beckett AH
    (1973) Species variation in the metabolism of R-(+)- and S-(-)-nicotine by alpha-C- and N-oxidation in vitro. Xenobiotica 3:573–580.
    OpenUrlPubMed
  193. ↵
    1. Jiménez-Ruiz CA,
    2. Barrios M,
    3. Peña S,
    4. Cicero A,
    5. Mayayo M,
    6. Cristóbal M, and
    7. Perera L
    (2013) Increasing the dose of varenicline in patients who do not respond to the standard dose. Mayo Clin Proc 88:1443–1445.
    OpenUrl
  194. ↵
    1. Johnson MW and
    2. Bickel WK
    (2003) The behavioral economics of cigarette smoking: the concurrent presence of a substitute and an independent reinforcer. Behav Pharmacol 14:137–144.
    OpenUrlCrossRefPubMed
  195. ↵
    1. Johnson MW,
    2. Garcia-Romeu A,
    3. Cosimano MP, and
    4. Griffiths RR
    (2014) Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 28:983–992.
    OpenUrlCrossRefPubMed
  196. ↵
    1. Johnson MW,
    2. Garcia-Romeu A, and
    3. Griffiths RR
    (2017) Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse 43:55–60.
    OpenUrl
  197. ↵
    1. Johnson PM,
    2. Hollander JA, and
    3. Kenny PJ
    (2008) Decreased brain reward function during nicotine withdrawal in C57BL6 mice: evidence from intracranial self-stimulation (ICSS) studies. Pharmacol Biochem Behav 90:409–415.
    OpenUrlCrossRefPubMed
  198. ↵
    1. Johnson RE,
    2. Hollis JF,
    3. Stevens VJ, and
    4. Woodson GT
    (1991) Patterns of nicotine gum use in a health maintenance organization. DICP 25:730–735.
    OpenUrlCrossRefPubMed
  199. ↵
    1. Jones CN,
    2. Howard JL, and
    3. McBennett ST
    (1980) Stimulus properties of antidepressants in the rat. Psychopharmacology (Berl) 67:111–118.
    OpenUrlCrossRefPubMed
  200. ↵
    1. Jorenby DE,
    2. Smith SS,
    3. Fiore MC,
    4. Hurt RD,
    5. Offord KP,
    6. Croghan IT,
    7. Hays JT,
    8. Lewis SF, and
    9. Baker TB
    (1995) Varying nicotine patch dose and type of smoking cessation counseling. JAMA 274:1347–1352.
    OpenUrlCrossRefPubMed
  201. ↵
    1. Jung M,
    2. Perio A,
    3. Worms P, and
    4. Soubrie P
    (1988) Pharmacological characterization of the physostigmine stimulus in rats. Psychopharmacology (Berl) 95:553–555.
    OpenUrlPubMed
  202. ↵
    1. Jutkiewicz EM,
    2. Brooks EA,
    3. Kynaston AD,
    4. Rice KC, and
    5. Woods JH
    (2011) Patterns of nicotinic receptor antagonism: nicotine discrimination studies. J Pharmacol Exp Ther 339:194–202.
    OpenUrlAbstract/FREE Full Text
  203. ↵
    1. Kaiser S and
    2. Wonnacott S
    (2000) alpha-bungarotoxin-sensitive nicotinic receptors indirectly modulate [(3)H]dopamine release in rat striatal slices via glutamate release. Mol Pharmacol 58:312–318.
    OpenUrlAbstract/FREE Full Text
  204. ↵
    1. Kalivas PW,
    2. Lalumiere RT,
    3. Knackstedt L, and
    4. Shen H
    (2009) Glutamate transmission in addiction. Neuropharmacology 56 (Suppl 1):169–173.
    OpenUrlCrossRefPubMed
  205. ↵
    1. Kamien JB and
    2. Woolverton WL
    (1989) A pharmacological analysis of the discriminative stimulus properties of d-amphetamine in rhesus monkeys. J Pharmacol Exp Ther 248:938–946.
    OpenUrlAbstract/FREE Full Text
  206. ↵
    1. Kasliwal R,
    2. Wilton LV, and
    3. Shakir SA
    (2009) Safety and drug utilization profile of varenicline as used in general practice in England: interim results from a prescription-event monitoring study. Drug Saf 32:499–507.
    OpenUrlCrossRefPubMed
  207. ↵
    1. Kauer JA and
    2. Malenka RC
    (2007) Synaptic plasticity and addiction. Nat Rev Neurosci 8:844–858.
    OpenUrlCrossRefPubMed
  208. ↵
    1. Ke L,
    2. Eisenhour CM,
    3. Bencherif M, and
    4. Lukas RJ
    (1998) Effects of chronic nicotine treatment on expression of diverse nicotinic acetylcholine receptor subtypes. I. Dose- and time-dependent effects of nicotine treatment. J Pharmacol Exp Ther 286:825–840.
    OpenUrlAbstract/FREE Full Text
  209. ↵
    1. Keenan A and
    2. Johnson FN
    (1972) Development of behavioural tolerance to nicotine in the rat. Experientia 28:428–429.
    OpenUrlPubMed
  210. ↵
    1. Kelly DL,
    2. McMahon RP,
    3. Weiner E,
    4. Boggs DL,
    5. Dickinson D,
    6. Conley RR, and
    7. Buchanan RW
    (2008) Lack of beneficial galantamine effect for smoking behavior: a double-blind randomized trial in people with schizophrenia. Schizophr Res 103:161–168.
    OpenUrlCrossRefPubMed
  211. ↵
    1. Kenny PJ,
    2. Chartoff E,
    3. Roberto M,
    4. Carlezon WA Jr.., and
    5. Markou A
    (2009) NMDA receptors regulate nicotine-enhanced brain reward function and intravenous nicotine self-administration: role of the ventral tegmental area and central nucleus of the amygdala. Neuropsychopharmacology 34:266–281.
    OpenUrlCrossRefPubMed
  212. ↵
    1. Khoo SY,
    2. McNally GP, and
    3. Clemens KJ
    (2017) The dual orexin receptor antagonist TCS1102 does not affect reinstatement of nicotine-seeking. PLoS One 12:e0173967.
    OpenUrl
  213. ↵
    1. Kim JS,
    2. Padnya A,
    3. Weltzin M,
    4. Edmonds BW,
    5. Schulte MK, and
    6. Glennon RA
    (2007) Synthesis of desformylflustrabromine and its evaluation as an alpha4beta2 and alpha7 nACh receptor modulator. Bioorg Med Chem Lett 17:4855–4860.
    OpenUrlCrossRefPubMed
  214. ↵
    1. Kimmey BA,
    2. Rupprecht LE,
    3. Hayes MR, and
    4. Schmidt HD
    (2014) Donepezil, an acetylcholinesterase inhibitor, attenuates nicotine self-administration and reinstatement of nicotine seeking in rats. Addict Biol 19:539–551.
    OpenUrl
  215. ↵
    1. King JR,
    2. Ullah A,
    3. Bak E,
    4. Jafri MS, and
    5. Kabbani N
    (2018) Ionotropic and metabotropic mechanisms of allosteric modulation of α7 nicotinic receptor intracellular calcium. Mol Pharmacol 93:601–611.
    OpenUrlAbstract/FREE Full Text
  216. ↵
    1. Kleven MS,
    2. Anthony EW, and
    3. Woolverton WL
    (1990) Pharmacological characterization of the discriminative stimulus effects of cocaine in rhesus monkeys. J Pharmacol Exp Ther 254:312–317.
    OpenUrlAbstract/FREE Full Text
  217. ↵
    1. Klowden AJ,
    2. Ivankovich AD, and
    3. Miletich DJ
    (1978) Ganglionic blocking drugs: general considerations and metabolism. Int Anesthesiol Clin 16:113–150.
    OpenUrlPubMed
  218. ↵
    1. Kometer M,
    2. Schmidt A,
    3. Bachmann R,
    4. Studerus E,
    5. Seifritz E, and
    6. Vollenweider FX
    (2012) Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biol Psychiatry 72:898–906.
    OpenUrlCrossRefPubMed
  219. ↵
    1. Kometer M,
    2. Schmidt A,
    3. Jäncke L, and
    4. Vollenweider FX
    (2013) Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations. J Neurosci 33:10544–10551.
    OpenUrlAbstract/FREE Full Text
  220. ↵
    1. Koob GF
    (2008) A role for brain stress systems in addiction. Neuron 59:11–34.
    OpenUrlCrossRefPubMed
  221. ↵
    1. Kowal NM,
    2. Ahring PK,
    3. Liao VWY,
    4. Indurti DC,
    5. Harvey BS,
    6. O’Connor SM,
    7. Chebib M,
    8. Olafsdottir ES, and
    9. Balle T
    (2018) Galantamine is not a positive allosteric modulator of human α4β2 or α7 nicotinic acetylcholine receptors. Br J Pharmacol 175:2911–2925.
    OpenUrlCrossRef
  222. ↵
    1. Kruse AC,
    2. Kobilka BK,
    3. Gautam D,
    4. Sexton PM,
    5. Christopoulos A, and
    6. Wess J
    (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13:549–560.
    OpenUrlCrossRefPubMed
  223. ↵
    1. Kuang G,
    2. Wang X,
    3. Halldin C,
    4. Nordberg A,
    5. Långström B,
    6. Ågren H, and
    7. Tu Y
    (2016) Theoretical study of the binding profile of an allosteric modulator NS-1738 with a chimera structure of the α7 nicotinic acetylcholine receptor. Phys Chem Chem Phys 18:28003–28009.
    OpenUrl
  224. ↵
    1. Kumar R,
    2. Reavill C, and
    3. Stolerman IP
    (1987) Nicotine cue in rats: effects of central administration of ganglion-blocking drugs. Br J Pharmacol 90:239–246.
    OpenUrlPubMed
  225. ↵
    1. Kuryatov A,
    2. Berrettini W, and
    3. Lindstrom J
    (2011) Acetylcholine receptor (AChR) α5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (α4β2)2α5 AChR function. Mol Pharmacol 79:119–125.
    OpenUrlAbstract/FREE Full Text
  226. ↵
    1. Kyerematen GA,
    2. Morgan ML,
    3. Chattopadhyay B,
    4. deBethizy JD, and
    5. Vesell ES
    (1990) Disposition of nicotine and eight metabolites in smokers and nonsmokers: identification in smokers of two metabolites that are longer lived than cotinine. Clin Pharmacol Ther 48:641–651.
    OpenUrlPubMed
  227. ↵
    1. Lamb RJ and
    2. Griffiths RR
    (1990) Self-administration in baboons and the discriminative stimulus effects in rats of bupropion, nomifensine, diclofensine and imipramine. Psychopharmacology (Berl) 102:183–190.
    OpenUrlCrossRefPubMed
  228. ↵
    1. Lamb RJ and
    2. Henningfield JE
    (1989) Human d-amphetamine drug discrimination: testing with d-amphetamine and hydromorphone. NIDA Res Monogr 95:423–424.
    OpenUrlPubMed
  229. ↵
    1. Lancaster T and
    2. Stead LF
    (2000) Mecamylamine (a nicotine antagonist) for smoking cessation. Cochrane Database Syst Rev 2:CD001009.
    OpenUrl
  230. ↵
    1. Lau CE,
    2. Spear DJ, and
    3. Falk JL
    (1994) Acute and chronic nicotine effects on multiple-schedule behavior: oral and SC routes. Pharmacol Biochem Behav 48:209–215.
    OpenUrlPubMed
  231. ↵
    1. Le Foll B,
    2. Chakraborty-Chatterjee M,
    3. Lev-Ran S,
    4. Barnes C,
    5. Pushparaj A,
    6. Gamaleddin I,
    7. Yan Y,
    8. Khaled M, and
    9. Goldberg SR
    (2012) Varenicline decreases nicotine self-administration and cue-induced reinstatement of nicotine-seeking behaviour in rats when a long pretreatment time is used. Int J Neuropsychopharmacol 15:1265–1274.
    OpenUrlCrossRefPubMed
  232. ↵
    1. Le Foll B,
    2. Wertheim C, and
    3. Goldberg SR
    (2007) High reinforcing efficacy of nicotine in non-human primates. PLoS One 2:e230.
    OpenUrlCrossRefPubMed
  233. ↵
    1. Le Houezec J
    (2003) Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a review. Int J Tuberc Lung Dis 7:811–819.
    OpenUrlPubMed
  234. ↵
    1. Le Houezec J,
    2. Jacob P III., and
    3. Benowitz NL
    (1993) A clinical pharmacological study of subcutaneous nicotine. Eur J Clin Pharmacol 44:225–230.
    OpenUrlCrossRefPubMed
  235. ↵
    1. Lesage MG
    (2009) Toward a nonhuman model of contingency management: effects of reinforcing abstinence from nicotine self-administration in rats with an alternative nondrug reinforcer. Psychopharmacology (Berl) 203:13–22.
    OpenUrlPubMed