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 α5 nAChR subunit as high risk factors for developing alcohol dependence.
METHODS: Here, we evaluate the role of the α5* nAChR for ethanol (EtOH)-mediated behaviors using male α5+/+ and α5-/- 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 α5 subunit to be important in mediating the sedative effects of EtOH. The α5-/- mice showed slower recovery from EtOH-induced sleep, as measured by loss of righting reflex. Additionally, the α5-/- mice showed enhanced impairment to EtOH-induced ataxia. We found the initial sensitivity to EtOH and EtOH metabolism to be similar in both α5+/+ and α5-/- mice. Hence, the enhanced sedation is likely due to a difference in the acute tolerance of EtOH in α5-/- mice. However, the α5 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 α5-/- mice.
CONCLUSIONS: Together, our data suggest that the α5 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 α5 nAChR subunit.