Recent Advances in the Potential of Positive Allosteric Modulators of the GABAB Receptor to Treat Alcohol Use Disorder

Abstract

Aims The effects of alcohol on gamma-aminobutyric acid (GABA) transmission are key for the development and maintenance of alcohol use disorder (AUD). Previous research consistently indicates that GABAB receptor agonists such as baclofen can attenuate addiction-related behaviors in preclinical models of AUD. More importantly, baclofen has also shown promise in clinical studies, particularly in severely alcohol-dependent patients. However, despite this promise, other clinical studies have not confirmed its efficacy and chiefly, larger clinical trials have not been conducted. Therefore, with the exception of France, baclofen is not approved for the treatment of AUD in any other country. Furthermore, it is also important to keep in mind that some patients treated with baclofen may experience important side-effects, including sedation, drowsiness and sleepiness. Methods This short review will first discuss the history of baclofen for AUD treatment. We will then summarize preclinical behavioral results that have investigated the efficacy of GABAB PAMs for addiction treatment, with a special focus on our recent work that investigated the effects of ADX71441, a novel GABAB PAM, on several alcohol-related behaviors in rats that model important aspects of human AUD. Finally, in light of the recent criticism about the translational value of animal models of addiction, the specific translational potential of our work and of other preclinical studies that have unanimously reported the efficacy of GABAB PAMs to attenuate multiple alcohol-related behaviors will be discussed. Results Positive allosteric modulators (PAMs) of the GABAB receptor offer an attractive alternative approach to baclofen and have the potential to achieve mechanistic and therapeutic effects similar to GABAB agonists, while avoiding the tolerance and toxicity issues associated with baclofen. To date, all preclinical behavioral results have invariably shown the efficacy of GABAB PAMs for addiction treatment. Conclusions Preclinical studies indicate that GABAB PAMs have a higher therapeutic index than orthosteric agonists, at least in terms of mitigating the sedative effects of GABAB agonism. This predicts that GABAB PAMs have a high translational potential in humans and merit being tested clinically, in particular in patients with severe AUD.

Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking

“…Effects observed only in excessive bingers could result from a floor effect, so that moderate binging could not be reduced. To assess this possibility, we tested systemic administration of baclofen, a GABAB agonist that has shown promise against alcohol drinking in some human studies [171]. Indeed, baclofen dosedependently reduced alcohol drinking in all animals, regardless of basal drinking levels, which likely occurs at a site other than the NAcb shell.…”

Molecular mechanisms of metabotropic GABA B receptor function

“…They have little to no intrinsic activity and open up chemical space and the possibility for specific receptor modulation without being constrained to the endogenous ligand chemotype. Their ability to fine-tune receptor response to endogenous agonists where physiologically relevant, and to potentiate effects of co-administered exogenous agonists, minimizes their abuse potential and makes them a sought-after class of compounds for clinical applications (112)(113)(114). In case of GABA B receptor, a number of PAMs have been identified (Fig.…”

Neurobiology of alcohol seeking behavior

“…Both pre-and postsynaptic activation of GABA B receptors inhibit neurotransmitter release through neuronal hyperpolarization, which results from increased potassium and decreased calcium permeability (Bettler & Tiao, 2006). Preclinical and clinical evidence suggests that activation of GABA B receptors holds promise as a mechanism for treatment of alcohol addiction (Addolorato et al, 2009;Augier, 2021;Farokhnia et al, 2018;Heilig & Egli, 2006).…”

“…Clinically, baclofen has shown promising, although conflicting, results for the treatment of alcohol addiction (Addolorato et al, 2007;Pierce et al, 2018;; see also Augier, 2021 for review on this topic), but safety and tolerability concerns have prevented its approval as a clinical alcohol addiction treatment (ANSM, 2017;Bowery, 2006;Garbutt, 2018). Some of these concerns are related to tolerance and dose-escalation, phenomena expected with chronic GPCR agonist treatment.…”

“…PAMs of the GABA B receptor have the potential to avoid these effects, by targeting a site that is topographically distinct from the orthosteric GABA binding sites, and instead potentiating the effect of GABA upon its binding to the receptor (Froestl, 2010;Perdona et al, 2011). GABA B PAMs have received considerable interest as potential therapeutics for alcohol addiction in recent years (Augier, 2021;Holtyn & Weerts, 2020;.…”