GABA Receptors and Alcohol Use Disorders: Preclinical Studies.

Preclinical research over the past several decades has demonstrated a role for the γ-aminobutyric acid (GABA) receptor in alcohol use disorder (AUD). This chapter offers an examination of preclinical evidence on the role of the GABA receptor on alcohol-related behaviors with a particular focus on the GABA receptor agonist baclofen, for which effects have been most extensively studied, and positive allosteric modulators (PAMs) of the GABA receptor. Studies employing rodent and non-human primate models have shown that activation of the GABA receptor can reduce (1) stimulating and rewarding effects of alcohol; (2) signs of alcohol withdrawal in rats made physically dependent on alcohol; (3) acquisition and maintenance of alcohol drinking under a two-bottle alcohol versus water choice procedure; (4) alcohol intake under oral operant self-administration procedures; (5) motivational properties of alcohol measured using extinction and progressive ratio procedures; (6) the increase in alcohol intake after a period of alcohol abstinence (the alcohol deprivation effect or ADE); and (7) the ability of alcohol cues and stress to reinstate alcohol seeking when alcohol is no longer available. Baclofen and GABA PAMs reduce the abovementioned behaviors across different preclinical models, which provides strong evidence for a significant role of the GABA receptor in alcohol-related behaviors and supports development of medications targeting GABA receptors for the treatment of AUD. This chapter highlights the value of examining mechanisms of alcohol-related behaviors across multiple animal models to increase the confidence in identification of new therapeutic targets.