The α5 Neuronal Nicotinic Acetylcholine Receptor Subunit Plays an Important Role in the Sedative Effects of Ethanol But Does Not Modulate Consumption in Mice

Background Alcohol use disorders (AUDs) are a major public health problem, and the few treatment options available to those seeking treatment offer only modest success rates. There remains a need to identify novel targets for the treatment of AUDs. The neuronal nicotinic acetylcholine receptors (nAChRs) represent a potential therapeutic target in the brain, as recent human genetic studies have implicated gene variants in the 5 nAChR subunit as high risk factors for developing alcohol dependence. Methods Here, we evaluate the role of the 5* nAChR for ethanol (EtOH)-mediated behaviors using male 5+/+ and 5/ transgenic mice. We characterized the effect of hypnotic doses of EtOH and investigated drinking behavior using an adapted drinking-in-the-dark (DID) paradigm that has been shown to induce high EtOH consumption in mice. Results We found the 5 subunit to be important in mediating the sedative effects of EtOH. The 5/ mice showed slower recovery from EtOH-induced sleep, as measured by loss of righting reflex. Additionally, the 5/ mice showed enhanced impairment to EtOH-induced ataxia. We found the initial sensitivity to EtOH and EtOH metabolism to be similar in both 5+/+ and 5/ mice. Hence, the enhanced sedation is likely due to a difference in the acute tolerance of EtOH in 5/ mice. However, the 5 subunit did not play a role in EtOH consumption for EtOH concentrations ranging from 5 to 30% using the DID paradigm. Additionally, varenicline was effective in reducing EtOH intake in 5/ mice. Conclusions Together, our data suggest that the 5 nAChR subunit is important for the sedative effects of EtOH but does not play a role in EtOH consumption in male mice. Varenicline can be a treatment option even when there is loss of function of the 5 nAChR subunit.