Activation of alpha 4(star) 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: 6.75). 07/2010; 30(30):10169-76. DOI: 10.1523/JNEUROSCI.2601-10.2010
Source: PubMed

ABSTRACT 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.


Available from: Rubing Zhao-Shea, Sep 15, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Binge ethanol consumption has widespread negative consequences for global public health. Rodent models offer exceptional power to explore the neurobiology underlying and affected by binge-like drinking as well as target potential prevention, intervention, and treatment strategies. An important characteristic of these models is their ability to consistently produce pharmacologically-relevant blood ethanol concentration. This review examines the current available rodent models of voluntary, pre-dependent binge-like ethanol consumption and their utility in various research strategies. Studies have demonstrated that a diverse array of neurotransmitters regulate binge-like drinking, resembling some findings from other drinking models. Furthermore, repeated binge-like drinking recruits neuroadaptive mechanisms in mesolimbocortical reward circuitry. New opportunities that these models offer in the current context of mechanistic research are also discussed. Copyright © 2015. Published by Elsevier Inc.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2015; DOI:10.1016/j.pnpbp.2015.05.012 · 4.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Varenicline, a smoking-cessation agent, may be useful in treating alcohol use disorders. An important consideration when studying factors that influence drinking/relapse is influence of the pharmacological effects of alcohol on these behaviors. Pre-exposure to alcohol (priming) can increase craving, drinking, and seeking behaviors. The primary goal of this work was to determine the effects of varenicline on alcohol-primed self-administration and seeking behavior in male Long-Evans rats. First, we assessed whether varenicline (0, 0.3, 1, 3 mg/kg, IP) has alcohol-like discriminative stimulus effects and whether varenicline alters sensitivity to alcohol in rats trained to discriminate a moderate alcohol dose (1 g/kg, IG) vs. water. Second, animals trained to self-administer alcohol underwent assessments to test the effects of: (i) varenicline (0, 0.3, 1, 3 mg/kg, IP) on self-administration, (ii) alcohol priming (0, 0.3, 1 g/kg, IG) on self-administration and seeking behavior, and (iii) varenicline (1 mg/kg) in combination with alcohol priming (1 g/kg) on these behaviors. Varenicline did not substitute for alcohol but disrupted the expression of sensitivity to alcohol. Varenicline decreased self-administration but only at a motor-impairing dose (3 mg/kg). Alcohol priming decreased self-administration and seeking behavior. Varenicline (1 mg/kg) blocked this effect under self-administration conditions, but not seeking conditions, which effectively resulted in increased alcohol intake. These findings suggest the importance of further behavioral and mechanistic studies to evaluate the use of varenicline in treating alcohol use disorders and its potential impact on drinking patterns in smokers using varenicline as a smoking-cessation aid.
    Psychopharmacology 02/2015; DOI:10.1007/s00213-015-3878-1 · 3.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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; DOI:10.1038/npp.2015.54 · 7.83 Impact Factor