Nicotinic Acetylcholine Receptors Containing α6 Subunits Contribute to Alcohol Reward-Related Behaviors

Evidence is emerging that neuronal nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine (DA) system are involved in mediating the reinforcing effects of alcohol. Midbrain DA neurons express high levels of α6 subunit-containing nAChRs that modulate DA transmission, implicating their involvement in reward-related behaviors. The present study assessed the role of α6-containing nAChRs in modulating alcohol reward using transgenic mice expressing mutant, hypersensitive α6 nAChR subunits (α6L9′S mice). α6L9′S mice and littermate controls were tested in three wellestablished models of alcohol reward: 24-hr two-bottle choice drinking, drinking in the dark (DID), and conditioned place preference (CPP). Confocal microscopy and patchclamp electrophysiology were used to demonstrate the localization and function of hypersensitive α6 subunit-containing nAChRs. Results indicate that female α6L9′S mice showed significantly higher alcohol intake at low concentrations of alcohol (3% and 6%) in the two-bottle choice procedure. Both male and female α6L9′S mice drank significantly more in the DID procedure and displayed an alcohol-induced place preference using a low dose of alcohol (0.5 g/kg) that was ineffective in littermate controls. Confocal microscopy showed that α6 subunit-containing nAChRs are selectively expressed on ventral tegmental area (VTA) DAergic, but not GABAergic neurons. Patch-clamp electrophysiology demonstrated that VTA DA neurons of α6L9′S mice are hypersensitive to ACh. Collectively, these results suggest that α6L9′S mice are more sensitive to the rewarding effects of alcohol, and suggest that VTA α6 subunitcontaining nAChRs modulate alcohol reward. Thus, α6 subunit-containing nAChRs may be a promising therapeutic target for treatment of alcohol use disorders.