Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice

摘要

Evidence suggests that there is an association between polymorphisms in the alpha 5 nicotinic acetylcholine receptor (nAChR) subunit and risk of developing alcohol dependence in humans. The alpha 5 nAChR subunit has also recently been shown to modulate some of the acute response to ethanol in mice. The aim of the current study was to further characterize the role of alpha 5-containing (alpha 5*) nAChRs in acute ethanol responsive behaviors, ethanol consumption and ethanol preference in mice. We conducted a battery of tests in male alpha 5 knockout (KO) mice for a range of ethanol-induced behaviors including hypothermia, hypnosis, and anxiolysis. We also investigated the effects of alpha 5* nAChR on ethanol reward using the Conditioned Place Preference (CPP) assay. Further, we tested the effects of gene deletion on drinking behaviors using the voluntary ethanol consumption in a two-bottle choice assay and Drinking in the Dark (DID, with or without stress) paradigm. We found that deletion of the alpha 5 nAChR subunit enhanced ethanol-induced hypothermia, hypnosis, and an anxiolytic-like response in comparison to wild-type controls. The alpha 5 KO mice showed reduced CPP for ethanol, suggesting that the rewarding properties of ethanol are decreased in mutant mice. Interestingly, Chrna5 gene deletion had no effect on basal ethanol drinking behavior, or ethanol metabolism, but did decrease ethanol intake in the DID paradigm following restraint stress. Taken together, we provide new evidence that alpha 5 nAChRs are involved in some but not all of the behavioral effects of ethanol. Our results highlight the importance of nAChRs as a possible target for the treatment of alcohol dependence. (C) 2018 Published by Elsevier Ltd.