Baclofen, a
GABA-B receptor agonist, is a promising treatment for
alcohol use disorder (AUD). Its mechanism of action in this condition is unknown.
GABA-B receptors interact with many
biological systems potentially involved in AUD, including transduction pathways and
neurotransmitter systems. Preclinical studies have shown that
GABA-B receptors are involved in memory storage and retrieval, reward, motivation, mood and anxiety; neuroimaging studies in humans show that
baclofen produces region-specific alterations in cerebral activity;
GABA-B receptor activation may have
neuroprotective effects;
baclofen also has anti-inflammatory properties that may be of interest in the context of addiction. However, none of these
biological effects fully explain the mechanism of action of
baclofen in AUD. Data from clinical studies have provided a certain number of elements which may be useful for the comprehension of its mechanism of action:
baclofen typically induces a state of indifference toward alcohol; the effective dose of
baclofen in AUD is extremely variable from one patient to another; higher treatment doses correlate with the severity of the addiction; many of the side effects of
baclofen resemble those of alcohol, raising the possibility that
baclofen acts as a
substitution drug; usually, however, there is no tolerance to the effects of
baclofen during long-term AUD treatment. In the present article, the
biological effects of
baclofen are reviewed in the light of its clinical effects in AUD, assuming that, in many instances, clinical effects can be reliable indicators of underlying biological processes. In conclusion, it is proposed that
baclofen may suppress the Pavlovian association between cues and rewards through an action in a critical part of the dopaminergic network (the amygdala), thereby normalizing the functional connectivity in the reward network. It is also proposed that this action of
baclofen is made possible by the fact that
baclofen and alcohol act on similar brain systems in certain regions of the brain.