GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence

The present paper summarizes the preclinical and clinical studies conducted to define the "anti-alcohol" pharmacological profile of the prototypic GABA(B) receptor agonist, baclofen, and its therapeutic potential for treatment of alcohol use disorder (AUD). Numerous studies have reported baclofen-induced suppression of alcohol drinking (including relapse- and binge-like drinking) and alcohol reinforcing, motivational, stimulating, and rewarding properties in rodents and monkeys. The majority of clinical surveys conducted to date including case reports, retrospective chart reviews, and randomized placebo-controlled studies suggest the ability of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. The recent identification of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, represents a novel, and likely more favorable, option for pharmacological manipulations of the GABA(B) receptor. Accordingly, data collected to date suggest that positive allosteric modulators of the GABA(B) receptor reproduce several "anti-alcohol" effects of baclofen and display a higher therapeutic index (with larger separation in terms of doses between "anti-alcohol" effects and sedation).