Suppressing Effect of Baclofen on Multiple Alcohol-Related Behaviors in Laboratory Animals

Abstract

This paper summarizes the several lines of experimental evidence demonstrating the ability of the prototypic GABAB receptor agonist, baclofen, to suppress multiple alcohol-related behaviors in laboratory rodents and non-human primates exposed to validated experimental models of alcohol use disorder (AUD). Specifically, treatment with baclofen has repeatedly been reported to suppress alcohol-induced locomotor stimulation, alcohol drinking (including binge- and relapse-like drinking), operant oral alcohol self-administration, alcohol seeking, and reinstatement of alcohol seeking in rats and mice. Treatment with baclofen also reduced operant oral alcohol self-administration in baboons. Several of these effects appear to be mediated by GABAB receptors located in the ventral tegmental area. The often observed co-occurrence of “desired” pharmacological effects and “unwanted” sedative effects represents the major drawback of the preclinical, anti-alcohol profile of baclofen. Collectively, these data underline the role of the GABAB receptor in the mediation of several alcohol-related behaviors. These data possess remarkable translational value, as most of the above effects of baclofen have ultimately been reproduced in AUD patients.

Baclofen decreases compulsive alcohol drinking in rats characterised by reduced levels of GAT-3 in the central amygdala

“…Indeed, down-regulation of GAT-3 in rats showing addiction-like behaviours results in an increased GABAergic tone in the CeA, presumably as the result of decreased GABA clearance by these GABA transporters in the synaptic cleft 17 . Pharmacological activation of GABA B receptors by the agonist baclofen decreases the extracellular release of GABA 23,24 , and results in a dose-dependent decrease in alcohol intake at the population level, as shown in this and in previous studies 6 . Furthermore, as shown in the present study, baclofen selectively decreased the compulsive drinking of alcohol by AAR rats when challenged by adulteration with quinine.…”

“…Many preclinical and clinical studies have highlighted the important involvement of the gamma-aminobutyric acid (GABA) system in the regulation of the reinforcing properties of alcohol and in the development of AUD. Pharmacological manipulations of GABAergic transmission through targeting both GABA A and GABA B receptors, influence different behavioural responses to alcohol, including alcohol self-administration, voluntary alcohol drinking, relapse-like and binge-like alcohol drinking, and the motivation for alcohol [6][7][8][9][10] . Furthermore, alterations in the expression of genes encoding some GABA A and GABA B receptor subunits, as well as GABA transporters, have been shown to influence the predisposition to high alcohol consumption and vulnerability to AUD in humans, as well as AUD-like behaviour in rodents 11,12 .…”

“…Activation of GABA B receptors has been shown to prevent preparatory and consummatory responses for alcohol, such as, the acquisition and maintenance of voluntary alcohol drinking, binge-like alcohol drinking and instrumental responding for alcohol 6,[8][9][10] . Adaptations to chronic alcohol exposure such as the alcohol deprivation effect and the reinstatement of the extinguished alcohol seeking behaviour are also prevented by GABA B receptor activation 6,8 . However, the influence of GABA B receptor agonists on compulsive alcohol drinking behaviour, a characteristic of AUD, has not yet been investigated.…”

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective

“…The wide use of baclofen as a myorelaxant has provided detailed information on its safety and side effects in these patients (17). From the 1970s, research, largely in animal addiction models, suggested that baclofen may also be effective in the treatment of AUD (1).…”

“…After promising preclinical evidence [for review see Colombo and Gessa (1)], clinical studies started to investigate whether baclofen may be useful in the treatment of alcohol use disorder (AUD). However, to date, clinical studies have yielded conflicting results.…”