Activation of 4* nAChRs is Necessary and Sufficient for Varenicline-Induced Reduction of Alcohol Consumption

Brudnick Neuropsychiatric Research Institute, and Program In Neuroscience, University of Massachusetts Medical School, 303 Belmont Street, Worcester, MA 01604, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2010; 30(30):10169-76. DOI: 10.1523/JNEUROSCI.2601-10.2010
Source: PubMed


Recently, the smoking cessation therapeutic varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to reduce alcohol consumption. However, the mechanism and nAChR subtype(s) involved are unknown. Here we demonstrate that varenicline and alcohol exposure, either alone or in combination, selectively activates dopaminergic (DAergic) neurons within the posterior, but not the anterior, ventral tegmental area (VTA). To gain insight into which nAChR subtypes may be involved in the response to alcohol, we analyzed nAChR subunit gene expression in posterior VTA DAergic neurons. Ethanol-activated DAergic neurons expressed higher levels of alpha4, alpha6, and beta3 subunit genes compared with nonactivated neurons. To examine the role of nicotinic receptors containing the alpha4 subunit (alpha4* nAChRs) in varenicline-induced reduction of alcohol consumption, we examined the effect of the drug in two complementary mouse models, a knock-out line that does not express the alpha4 subunit (alpha4 KO) and another line that expresses alpha4* nAChRs hypersensitive to agonist (Leu9'Ala). While varenicline (0.1-0.3 mg/kg, i.p.) reduced 2% and 20% alcohol consumption in wild-type (WT) mice, the drug did not significantly reduce consumption in alpha4 KO animals. Conversely, low doses of varenicline (0.0125-0.05 mg/kg, i.p.) that had little effect in WT mice dramatically reduced ethanol intake in Leu9'Ala mice. Infusion of varenicline into the posterior, but not the anterior VTA was sufficient to reduce alcohol consumption. Together, our data indicate that activation of alpha4* nAChRs is necessary and sufficient for varenicline reduction of alcohol consumption.

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Available from: Rubing Zhao-Shea, Sep 15, 2014
    • "Pre-clinical studies have demonstrated that varenicline decreases both operant and home cage alcohol self-administration in rodents (Kamens et al., 2010; Steensland et al., 2007) and, recently, clinical evidence indicating reduced drinking in a population of heavy-drinking smokers or primary alcoholic patients treated with varenicline have started to emerge (Childs et al., 2012; Fucito et al., 2011; Litten et al., 2013; McKee et al., 2009; Mitchell et al., 2012). These well-documented anti-alcohol properties of varenicline seem to be dependent on the activation of 4 nAChRs (Hendrickson et al., 2010). In contrast, 7 (Kuzmin et al., 2009) and 34 nAChRs (Carnicella et al., 2010; Cippitelli et al., 2015b) may not be involved in alcohol reinforcement. "
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    ABSTRACT: Background: Alcohol and nicotine are largely co-abused. Here, we investigated whether concurrent exposure to both addictive drugs influences each other's consumption and whether varenicline attenuates alcohol consumption in the presence of nicotine. Methods: Marchigian Sardinian alcohol-preferring (msP) rats trained to simultaneously self-administer oral alcohol (10% v/v) and intravenous nicotine (30μg/kg/inf) were used. Additional groups of rats were trained to self-administer either alcohol or nicotine. Further, msP rats were also trained to self-administer nicotine followed by 22-h/day access to alcohol and water in a two bottle free choice paradigm or water alone. The effects of varenicline (0.0, 0.3, 1.0, 3.0mg/kg, p.o.) on alcohol and nicotine consumption were tested. Results: In a self-administration paradigm, msP rats showed a significantly high level of alcohol and nicotine intake when the drugs were administered alone. However, when access to both drugs occurred concomitantly, the number of nicotine infusions self-administered was significantly decreased. Nicotine self-administration was markedly reduced by varenicline regardless of whether it was self-administered alone or concurrently with alcohol. In a two bottle choice test, varenicline significantly decreased nicotine self-administration but had no influence on alcohol consumption. Conclusion: Varenicline is highly efficacious in decreasing nicotine self-administration either alone or in combination with alcohol. However, varenicline failed to influence both operant responding for alcohol and home-cage alcohol drinking in msP animals. Taken together, our findings suggest that the effects of varenicline could be specific to nicotine under conditions where excessive alcohol drinking is facilitated by genetic factors as in msP rats.
    Drug and Alcohol Dependence 09/2015; DOI:10.1016/j.drugalcdep.2015.09.002 · 3.42 Impact Factor
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    • "Although not previously examined, similar predictions of partial agonism/antagonism can be made about VAR within the reward circuitry. VAR has been broadly implicated in the reduction of reward signaling, selectively decreasing voluntary alcohol intake in both rodents (Hendrickson et al, 2010; Steensland et al, 2007) and humans (Fucito et al, 2011; McKee et al, 2009). Administration of VAR decreases subjective reports of nicotine craving (Brandon et al, 2011; Patterson et al, 2009) and smoking cue-induced activity in the medial OFC (Franklin et al, 2011) in nontreatmentseeking smokers. "
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    ABSTRACT: Recidivism rates for cigarette smokers following treatment often exceed 80%. Varenicline is the most efficacious pharmacotherapy currently available with cessation rates of 25-35% following a year of treatment. While the in vivo binding properties are well known, varenicline's neurobiological mechanisms of action are still poorly understood. Varenicline acts as a nicotinic receptor partial agonist or antagonist depending on the presence or absence of nicotine and has been implicated in the reduction of reward signaling more broadly. The current study probed anticipatory reward processing using a revised monetary incentive delay task during fMRI in cohorts of smokers and non-smokers who completed a two-drug, placebo-controlled, double-blind crossover study. All participants underwent ~17 days of order balanced varenicline and placebo pill administration and were scanned under each condition wearing a transdermal nicotine or placebo patch. Consistent with nicotine's ability to enhance the rewarding properties of nondrug stimuli, acute nicotine administration enhanced activation in response to reward-predicting monetary cues in both smokers and non-smokers. In contrast, varenicline reduced gain magnitude processing, but did so only in smokers. These results suggest that varenicline's down regulation of anticipatory reward processing in smokers, in addition to its previously demonstrated reduction in the negative affect associated with withdrawal, independently and additively alter distinct brain circuits. These effects likely contribute to varenicline's efficacy as a pharmacotherapy for smoking cessation.Neuropsychopharmacology accepted article preview online, 06 March 2015. doi:10.1038/npp.2015.54.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2015; 40(8). DOI:10.1038/npp.2015.54 · 7.05 Impact Factor
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    • "This shows that it is possible to reduce ethanol self-administration in rats by blocking ethanol-induced DA release via nAChRs in the VTA and by increasing accumbal DA release. It has been shown that intra-VTA varenicline infusions reduce ethanol consumption in mice after short-term ethanol exposure (Hendrickson et al., 2010), an unexpected finding from our study was that varenicline administered directly into the anterior or posterior VTA had no effect on ethanol consumption in long-term ethanol-consuming rats. The most likely explanation is the significant methodological differences between the studies such as the species, varenicline doses and BJP the duration of ethanol exposure prior to varenicline testing (days vs. months). "
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    ABSTRACT: BACKGROUND AND PURPOSE Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption. EXPERIMENTAL APPROACH Rats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV). KEY RESULTS Microinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc. CONCLUSION AND IMPLICATIONS Following long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption.
    British Journal of Pharmacology 03/2014; 171(14). DOI:10.1111/bph.12690 · 4.84 Impact Factor
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