Brudnick Neuropsychiatric Research Institute, Department of Psychiatry
Medical Subject Headings
Alanine; Alcohol Drinking; Analysis of Variance; Animals; Benzazepines; Central Nervous System Depressants; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drinking Behavior; Drug Combinations; Ethanol; Gene Expression Regulation; Leucine; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurons; Nicotinic Agonists; Proto-Oncogene Proteins c-fos; Quinoxalines; Receptors, Nicotinic; Tyrosine 3-Monooxygenase; Ventral Tegmental Area
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
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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Citation: Hendrickson LM, Zhao-Shea R, Pang X, Gardner PD, Tapper AR. Activation of alpha4* nAChRs is necessary and sufficient for varenicline-induced reduction of alcohol consumption. J Neurosci. 2010 Jul 28;30(30):10169-76. Link to article on publisher's website. Copyright © 2010 the authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/.