Abstract

Alcohol abuse leads to great medical, social, and economic burdens throughout the world. It is believed that the rewarding actions of alcohol are mediated by alterations in the mesolimbic dopaminergic system leading to increased levels of dopamine in the nucleus accumbens (NAc). Little is known about the role that ligand‐gated ion channels (LGICs), such as glycine receptors (GlyRs), have in regulating levels of ethanol intake and place preference. In this study, we used knock‐in (KI) mice that have ethanol‐insensitive α1 GlyRs (KK385/386AA) and a combination of electrophysiological and behavioral approaches to examine how expression of ethanol‐resistant α1 GlyRs in brain neurons might affect binge drinking and conditioned place preference. Data show that tonic α1 GlyR–mediated currents that modulate accumbal excitability were exclusively sensitive to ethanol only in wild‐type (WT) mice. Behavioral studies showed that the KI mice have a higher intake of ethanol upon first exposure to drinking and greater conditioned place preference to ethanol, suggesting that α1 GlyRs in the brain have a protective role against abuse. This study suggests that nonsynaptic α1–containing GlyRs have a role in motivational and early reinforcing effects of ethanol and open a novel opportunity for pharmacotherapy development to treat alcohol use disorders.