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

Abstract

Evidence suggests that there is an association between polymorphisms in the α5 nicotinic acetylcholine receptor (nAChR) subunit and risk of developing alcohol dependence in humans. The α5 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 α5-containing (α5*) nAChRs in acute ethanol responsive behaviors, ethanol consumption and ethanol preference in mice. We conducted a battery of tests in male α5 knockout (KO) mice for a range of ethanol-induced behaviors including hypothermia, hypnosis, and anxiolysis. We also investigated the effects of α5* 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 α5 nAChR subunit enhanced ethanol-induced hypothermia, hypnosis, and an anxiolytic-like response in comparison to wild-type controls. The α5 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 α5 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.

Profound alteration in reward processing due to a human polymorphism in CHRNA5: a role in alcohol dependence and feeding behavior

“…Alcoholics are three times more likely to smoke than the general population [3], and at higher risk to die from smokingrelated illnesses than from alcohol-related causes [35]. Several mechanisms have been proposed to underlie alcohol and tobacco addiction comorbidity, including cross-cue conditioning, cross-tolerance and -reinforcement [36,37] and nicotinic modulation of alcohol effects [30,38,39]. Both alcohol and nicotine can modulate signalling pathways implicated in addiction through both distinct and common molecular targets.…”

“…In fact, EtOH has been shown to act as an allosteric modulator of nAChRs and suggested to alter the balance between activation and desensitization of nAChRs caused by nicotine [30]. Previous studies reported no alterations in EtOH intake in α5 knock-out (KO) mice in a drinkingin-the-dark paradigm [38,40], although EtOH intake was actually decreased in these mice, in a similar paradigm, after a restraint stress [38]. The same study also reported decreased EtOH-induced conditioned place preference in α5 KO mice.…”

Concatemers to re-investigate the role of α5 in α4β2 nicotinic receptors

“…Genomic studies associate the α5 gene to smoking and lung cancer through the existence of a polymorphism that produces a protein variant of α5 (D398N) [1]. In mice, α4 -/and β2 -/genotypes fail to self-administer nicotine, while α5 -/genotype displays a unique altered behavior towards nicotine, with partly reduced nicotine-related behaviors [2][3][4] and also towards ethanol, whose effects are partly enhanced [5], together with anxiety-related behaviors [6]. In rats, a recent study also highlighted a phenotype linked to nicotine and alcohol relapse processes [7,8].…”

Identification of the Risk Genes Associated With Vulnerability to Addiction: Major Findings From Transgenic Animals

“…With respect to alcohol, α 5 KO mice show enhanced alcohol-induced hypothermia and anxiolysis, but reduced ethanol place preferences and reduced ethanol intake in the DID with restraint stress paradigm ( Dawson et al, 2018 ). By contrast, α 5 KO mice did not differ from wild type controls in the DID paradigm ( Santos et al, 2013 ), although they were more sensitive to the acutely sedating effects of ethanol ( Santos et al, 2013 ).…”