Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats

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Abstract

Background

Tobacco addiction is a relapsing disorder that constitutes a substantial worldwide health problem, with evidence suggesting that nicotine and nicotine-associated stimuli play divergent roles in maintaining smoking behavior in men and women. While animal models of tobacco addiction that utilize nicotine self-administration have become more widely established, systematic examination of the multiple factors that instigate relapse to nicotine-seeking have been limited. Here, we examined nicotine self-administration and subsequent nicotine-seeking in male and female Sprague-Dawley rats using an animal model of self-administration and relapse.

Methods

Rats lever pressed for nicotine (0.03 and 0.05 mg/kg/infusion, IV) during 15 daily 2-h sessions, followed by extinction of lever responding. Once responding was extinguished, we examined the ability of previously nicotine-paired cues (tone + light), the anxiogenic drug yohimbine (2.5 mg/kg, IP), a priming injection of nicotine (0.3 mg/kg, SC), or combinations of drug + cues to reinstate nicotine-seeking.

Results

Both males and females readily acquired nicotine self-administration and displayed comparable levels of responding and intake at both nicotine doses. Following extinction, exposure to the previously nicotine-paired cues or yohimbine, but not the nicotine-prime alone, reinstated nicotine-seeking in males and females. Moreover, when combined with nicotine-paired cues, both yohimbine and nicotine enhanced reinstatement. No significant sex differences or estrous cycle dependent changes were noted across reinstatement tests.

Conclusions

These results demonstrate the ability to reinstate nicotine-seeking with multiple modalities and that exposure to nicotine-associated cues during periods of a stressful state or nicotine can increase nicotine-seeking.

Introduction

Tobacco addiction constitutes a critical health issue, with an estimated 1.3 billion daily tobacco smokers worldwide (Guindon and Boisclair, 2003, Thun and da Costa e Silva, 2003). Despite a substantial decrease in the percentage of the population using tobacco over the last four decades, tobacco use remains the leading, preventable cause of premature death and disease in the United States, responsible for 440,000 deaths each year (Fellows et al., 2002). Similar to other drugs of abuse, one of the most significant problems for long-term treatment of nicotine dependence is the high incidence of relapse to drug-seeking and drug-taking following prolonged periods of abstinence. In fact, the majority of smokers who quit will relapse (Fiore, 2000, Shiffman et al., 1998), and nearly all smokers who relapse after an initial quit attempt will return to regular smoking (Brandon et al., 1990, Chornock et al., 1992, Kenford et al., 1994).

Three primary factors have been found to contribute to nicotine relapse in humans: nicotine-associated cues (Perkins et al., 1994, Perkins et al., 1999), stress (Brandon et al., 1990, Patton et al., 1997), and exposure to the drug itself (Chornock et al., 1992, Sofuoglu et al., 2005). Similarly, these trigger factors have been used in animal models of relapse to drug-seeking behavior, particularly in the extinction/reinstatement model following withdrawal from chronic nicotine self-administration, whereby exposure to nicotine-paired stimuli (LeSage et al., 2004, Liu et al., 2006, Liu et al., 2008), footshock stress (Buczek et al., 1999, Martin-Garcia et al., 2009, Yamada and Bruijnzeel, 2011, Zislis et al., 2007), or noncontingent nicotine administration (Le et al., 2006, Martin-Garcia et al., 2009, Shaham et al., 1997, Shram et al., 2008) will reinstate nicotine-seeking as measured by responding on a previously nicotine-paired lever.

While animal models of nicotine addiction have increasingly been utilized, a number of unanswered questions remain, including the issue of sex differences in nicotine-taking and -seeking. This constitutes an important clinical issue, as it has been demonstrated that female smokers progress more rapidly from casual use to dependence, have fewer and shorter abstinence periods, and have a more difficult time remaining abstinent (see Perkins, 2001 for review). Similarly, preclinical evidence suggests some degree of enhanced motivation for nicotine/nicotine-associated cues in female rats. In one study, females exhibited greater responding for nicotine (0.02 mg/kg) under a fixed ratio 5 (FR5) and progressive ratio (PR) schedules of reinforcement (Donny et al., 2000). Similar enhancements in FR acquisition and PR responding for low doses of nicotine (0.005 mg/kg) have also been noted for female adolescent rats (Lynch, 2009), and enhanced oral nicotine self-administration has been reported for adolescent female mice (Klein et al., 2004). In another study, Chaudhri et al. (2005) noted enhanced FR5 responding in female rats that self-administered higher doses of nicotine (i.e., ≥0.06 mg/kg) alone. When nicotine infusions were paired with a conditioned stimulus (i.e., 1 s presentation of a cue light, followed by 60 s offset of the houselight), significant increases in responding were noted for lower doses of nicotine (i.e., ≤0.06 mg/kg) in both sexes, an effect that was greater in females. In addition to highlighting the prominent contribution of nicotine-paired stimuli to enhance nicotine reinforcement, these results collectively suggest that females may be more motivated to obtain nicotine and may be more sensitive to the effects of nicotine-paired stimuli.

Despite the initial research examining sex differences in nicotine self-administration, no studies to date have examined reinstatement of nicotine-seeking in females, nor examined sex differences in reinstatement. Moreover, although clinical research suggests that the menstrual cycle in women can affect craving and propensity to relapse following abstinence (Allen et al., 2008, Carpenter et al., 2006, Franklin et al., 2004), it has not been determined whether nicotine-seeking in rats may vary as a function of the estrous cycle. Here, we investigated the role of sex and estrous cycle in mediating nicotine-taking and nicotine-seeking using a model of nicotine self-administration and relapse in male and freely cycling female rats. Moreover, we examined the separate, as well as interactive, effects of nicotine-paired cues, a pharmacological stressor (yohimbine), and noncontingent nicotine administration on reinstatement of nicotine-seeking in male and female rats. Yohimbine is a norepinephrine (NE) α2 receptor antagonist that increases NE release in several neural structures implicated in stress, including the bed nucleus of the stria terminalis (Forray et al., 1997) and the amygdala (Khoshbouei et al., 2002), and has been shown to produce stress-like responses (e.g., increases in subjective anxiety, blood pressure, and sympathetic symptoms) in humans (Charney et al., 1983, Holmberg and Gershon, 1961) and to induce craving in abstinent drug-dependent subjects (Stine et al., 2002). Similarly, yohimbine produces stress activation (e.g., increases in plasma corticosterone, arterial blood pressure, heart rate, and potentiated startle response) in animals (Davis et al., 1979, Lang and Gershon, 1963, Suemaru et al., 1989) and reinstates drug-seeking for heroin (Banna et al., 2010), alcohol (Gass and Olive, 2007, Le et al., 2005), methamphetamine (Shepard et al., 2004), and cocaine (Anker and Carroll, 2010, Bongiovanni and See, 2008, Feltenstein et al., 2011, Feltenstein and See, 2006). Moreover, yohimbine has been shown to enhance cue-induced reinstatement of heroin- (Banna et al., 2010) and cocaine-seeking (Buffalari and See, 2011, Feltenstein et al., 2011, Feltenstein and See, 2006).

Section snippets

Subjects

Aged-matched male (initial weight 250–300 g, P59–67) and female (initial weight 175–225 g, P57–74) Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA, USA) were individually housed in separate temperature- and humidity-controlled vivariums on a reverse 12 h light-dark cycle (lights off at 06:00). All experimental procedures occurred between 07:00 and 16:00. In the home cage, animals had access to water ad libitum and were maintained on a controlled diet (20–25 g/day) of standard rat

Nicotine self-administration and extinction

Rats readily acquired nicotine self-administration, responded preferentially on the nicotine-paired lever and displayed stable lever responding (Fig. 1). For both doses of nicotine, active lever responding was significantly greater than inactive lever responding (Fs1,108–124 = 112.00–116.43, ps < 0.001), but no significant differences in active lever presses were noted for the sex or day main effects, or for the sex by day interactions. Inactive lever responding was uniformly low in both males and

Discussion

To date, very few studies have examined potential sex differences and the role of the estrous cycle in preclinical models of nicotine addiction, and have primarily focused on the time of active nicotine self-administration (Chaudhri et al., 2005, Donny et al., 2000, Lynch, 2009). In addition to examining nicotine self-administration, the current study characterized reinstatement of extinguished nicotine-seeking following prolonged withdrawal in both male and female rats. Although we did not

Role of funding source

The authors declare no role of the funding sources.

Contributors

MWF designed the experiments, assisted in the animal surgeries and the experimental procedures, performed statistical analyses, and wrote the manuscript. SMG performed the animal surgeries and experimental procedures. RES designed the experiment and wrote the manuscript.

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgements

The authors would like to thank Dr. Cassandra Gipson for providing insightful comments. This research was supported by NIDA Grant DA016511 (RES), NICHHD Grant K12 HD055885-01 (MWF), and NIH Grant C06 RR015455.

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