The role of nicotinic acetylcholine receptors in ethanol responsive behaviors and drinking.

摘要

The high co-morbidity between alcohol (ethanol) and nicotine abuse suggests that nicotinic acetylcholine receptors (nAChRs), which are thought to underlie nicotine dependence, may also be involved in alcohol dependence. A genomic region that encodes the 5* nAChR subtype has recently been shown to be associated with alcohol dependence phenotypes in humans. Therefore, the aim of this study was to determine the role of α5* nAChRs in ethanol-responsive behaviors upon acute administration in mice as well as in their drinking behavior. We conducted tests in mice lacking the α5 coding gene (Chrna5) in ethanol-induced hypothermia, hypnosis, anxiolysis, and conditioned place preference. We also assessed drinking behavior in these mice using models of voluntary ethanol consumption, two-bottle choice preference and intermittent access, as well as acute binge drinking behavior in the Drinking-in-the-Dark paradigm. Our results showed that deletion of the α5 gene enhanced acute behaviors, including ethanol-induced hypothermia, hypnosis recovery time, and the anxiolytic-like response in mice. We also found that α5 gene deletion resulted in decreased ethanol CPP, but had no effect on ethanol consumption in either model of drinking behavior tested under normal conditions. However, we discovered that under conditions of stress from multiple daily injections of saline or nicotine, Drinking-in-the-Dark intake was reduced in α5 null mutant mice. We also examined the role of β2* nAChRs due to the tendency of the α5 subunit to be co-expressed with this subtype, which also plays an important role in nicotine dependence. Our results showed that pharmacological and genetic manipulation of β2* nAChRs modulated some acute alcohol-responsive behaviors, namely, hypnosis, recovery-time and the anxiolytic-like response produced by ethanol, but did not modulate ethanol drinking behavior in mice. These studies provide evidence that 5* subtypes and β2* subtypes, which play a critical role in nicotine dependence, also play a role in acute ethanol-responsive behaviors in vivo, thus supporting studies in humans that nicotine and alcohol dependence share common genetic components.