Invited reviewSerotonin at the nexus of impulsivity and cue reactivity in cocaine addiction
Introduction
Thirty years of intensive study have elucidated molecular mechanisms underlying the in vivo effects of abused substances, the impressive, distributed network of circuitry at the heart of addictive processes, and have made inroads into the complex polygenetic nature of addiction (Ducci and Goldman, 2012, Kalivas and Volkow, 2005, Koob and Volkow, 2010). These 30 years have produced increasingly sophisticated perspectives on addiction as a chronic, relapsing brain disorder that engages reward function and an ‘expanding cycle of dysfunction’ in cognition, learning and emotional functions (Volkow et al., 2010). This trajectory from drug use to addiction begins against a background of vulnerability based upon genetic and environmental factors, and progresses as neuronal plasticity in key brain circuits entrains addictive behaviors in concert with experiential learning and the added pharmacological impact of the abused substance. The means to reverse causal neuroplasticity and therapeutically improve function in the addicted brain is an important quest and one ripe with near-term therapeutic potential with positive outcomes. Although surprisingly less is known about its influence compared to key players dopamine (DA) and glutamate (Kalivas and Volkow, 2005), serotonin (5-hydroxytryptamine; 5-HT) neurotransmission in key neural circuits may contribute to inherent states of vulnerability as well as the altered neurobiological states that drive the transition from drug use to abuse to dependence. This review emphasizes the role of 5-HT in key addiction phenotypes and the implications of current findings to the future of therapeutics in addiction.
There are a multitude of factors that contribute to the initial decision to experience an abused drug, to the continued maintenance of drug use and the ultimate development of dependence or addiction. The same or even different factors may contribute to vulnerability to withdrawal-related syndromes, difficulty achieving abstinence, and sensitivity to relapse during abstinence. Relapse is a particularly challenging clinical problem as, even though a drug abuser may initiate termination of drug use and commit to abstinence, the recidivism rates can be very high (Brandon et al., 2007). Relapse is defined as reversion to drug-using behavior which interrupts the progress of abstinence and can be seen as a dynamic process rather than a single, discrete event (Maisto and Connors, 2006, Miller et al., 1996). Vulnerability to endogenous factors (e.g., craving, stress, withdrawal) is interwoven with responsiveness to exogenous stimuli (e.g., drug-associated cues) which can serve as immediate antecedents to relapse (Hendershot et al., 2011). Efficacious relapse prevention programs emphasize cognitive-behavioral skills and coping responses with an accent on environmental stimuli and cognitive processes as triggers (Hendershot et al., 2011). Medications are also useful to suppress relapse which requires reestablishment of normal brain function consequent to long-term, drug-induced neuroplasticity and diminishment of the power of relapse triggers (Modesto-Lowe and Kranzler, 1999, Paterson, 2011). Currently, medications for treatment of opioid (heroin, morphine) and alcohol addiction which help to suppress relapse in the context of behavioral therapy have been developed. However, although nicotine replacement therapy, bupropion and varenicline are effective therapeutics for nicotine addictions, medication development efforts have not yet yielded effective pharmacotherapies for cocaine and other abused psychostimulants. A great deal of interest remains in filling this gap to maximize the probability of treatment success by minimizing lapses to drug use (Hendershot et al., 2011, Volkow and Skolnick, 2012).
Section snippets
Cocaine
The illicit abuse of psychostimulants is a problem that includes a myriad of abused chemical substances. The present review will focus on cocaine for several reasons. First, cocaine remains one of the greatest challenges on the public health agenda in the U.S. and the world. Indicators of the extent of the cocaine problem in the U.S. (e.g., forensic seizures, treatment, mortality and emergency department admissions) continue to dominate the landscape; serious health and social consequences of
Addiction neurocircuitry
Addiction is now recognized as a disordered integration of cognitive and motivational aspects of reward-directed behavior involving higher order limbic-corticostriatal circuit structures (Kalivas and Volkow, 2005). This circuit controls both impulsivity and cue reactivity and neuroadaptations in limbic-corticostriatal subnuclei are noted as particularly relevant in addiction (Feil et al., 2010, Fineberg et al., 2010, Kalivas and Volkow, 2005, Koob and Volkow, 2010). Several key regions
Serotonin
The 5-HT neurotransmitter system is integral in motor, cognitive, reward and affective function (Jacobs and Fornal, 1995, Lucki, 1998, Soubrié, 1986, Tops et al., 2009), processes that are under the control of dense 5-HT afferent input to the limbic-corticostriatal circuit afforded by 5-HT neurons originating in the dorsal (DRN) and medial (MRN) raphe nuclei (Kosofsky and Molliver, 1987, Lidov et al., 1980, Vertes and Linley, 2008). To understand the detailed interactions of 5-HT, 5-HT
Cocaine reward and serotonin
Food, water, sex or an abused drug can serve as a rewarding stimulus that positively reinforces, and increases the probability of, behavior leading to its consumption (Morse and Skinner, 1958). Multiple, somewhat distinguishable, facets of reward include hedonic value (‘liking’), the organism's motivation to approach and consume rewards (incentive salience; ‘wanting’), and the learning of predictive associations between the reward and allied internal/external stimuli (drug-associated stimuli) (
Impulsivity and serotonin
Impulsivity is not a unitary construct, but can be considered a “trait” comprised of several components that contribute to its characteristic pattern of poorly conceived, disadvantageous decisions and behaviors (Evenden, 1999a, Moeller et al., 2001a). Some of the components of impulsivity as a cognitive construct include maladaptive inhibitory control, failure to consider the consequences of behaviors, and a preference for immediate rather than delayed rewards (Evenden, 1999a, Moeller et al.,
Cocaine cue reactivity and serotonin
Drug-associated cues have long been hypothesized to be an essential driver in the cycle of addiction, relapse and recovery (Wikler, 1948), and psychological theorists have greatly enriched our understanding of the intertwined natures of drug reward and drug-related stimuli at behavioral and neuromolecular levels (Crombag et al., 2008, Kelley, 2004, Richard et al., 2012, Saunders and Robinson, 2013). Physiological responses (Robbins et al., 1997), and altered brain activation patterns in
Intersection of Impulsivity and Cue Reactivity in Cocaine Dependence
High impulsivity and cue reactivity are linked to an increased propensity to relapse (Moeller et al., 2001b, O'Brien et al., 1998) while studies suggest that these are interlocked phenotypes in humans (Liu et al., 2011) and animals (Anastasio et al., 2013b, Belin et al., 2008, Perry et al., 2005). Serotonin is a sensitive homeostatic regulator of these interlocked phenotypes as measured following manipulations which disrupt the 5-HT balance in the entire brain (e.g., 5,7-DHT, fluoxetine; Table 1
Implications for Treatment of Cocaine Addiction
Relapse is a major challenge to achievement of successful remission of cocaine addiction, and predictors of relapse and treatment success would be helpful to control addictive behaviors. Progress in understanding the neurobiology of vulnerability factors for relapse and identifying predictors of individual vulnerability are important steps in increasing opportunities for prevention of cocaine addiction. For example, the use of screening to identify maladaptive impulsivity could be helpful to
Future directions
Many questions remain concerning the explicit role of 5-HT receptors and transduction systems within key neural circuits in mediating impulsivity, cocaine reward and cocaine cue reactivity. There are several, overlapping mechanisms that could underlie the efficacy of either global changes in 5-HT efflux (after manipulation of 5-HT levels in brain) or following direct 5-HT receptor ligands which are incompletely understood, and here we illustrate several future investigations of interest to
Conclusions
We have entered the world of personalized medicine in which a patient's unique genetic and phenotypic profiles will ultimately provide the signposts to tailor diagnoses, maximize treatment success and reduce off-target and side effect profiles of treatments. The science in chronic diseases such as cancer is rapidly advancing in these goals to provide new targeted diagnostics and medications for treatment tailored to provide the best clinical response in an individual (Hamburg and Collins, 2010
Acknowledgments
This research was supported by the National Institute on Drug Abuse grants P20 DA024157 (KAC), R01 DA006511 (KAC), K05 DA020087 (KAC), K99 DA033374 (NCA) and the Jeane B. Kempner Postdoctoral Scholar Award (NCA). Dr. Cunningham is an editor of Neuropsychopharmacology Reviews for which she receives compensation from the American College of Neuropsychopharmacology, and is a consultant for Arena Pharmaceuticals. The authors thank Dr. F. Gerard Moeller for his translational guidance and Dr. Marcy
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