GABAergic Network Dysregulation in Alcohol Use Disorder: Receptor-Transporter Interactions Driving the Transition From Goal-Directed to Compulsive Behaviour

Alcohol use disorder (AUD) is characterized by a shift from controlled, goal-directed drinking to compulsive, habitual alcohol (a.k.a. ethanol) seeking, even in the face of negative outcomes. This transition is closely associated with alterations in cortico-striatal circuitry and dysregulated GABAergic signalling, both of which drive the progression from flexible control to compulsive behaviour. Acute alcohol exposure enhances GABAergic inhibition, primarily by increasing presynaptic GABA release. Chronic exposure leads to compensatory neuroadaptations, such as subunit reorganization, receptor internalization and diminished GABA receptor sensitivity. While these neuroadaptations alter receptor-mediated GABAergic signalling during dependence and withdrawal, they also alter dopaminergic regulation and further reinforce alcohol-seeking behaviour. Beyond receptor-level adaptations, impaired GABA clearance, especially through the astrocytic transporter GAT3, plays a crucial role in regulating extracellular GABA concentrations and tonic inhibition. This effect is particularly evident within the dorsal striatum, where elevated tonic GABA shifts control from flexible, goal-directed action towards rigid, habitual responding by altering the balance between the dorsomedial and dorsolateral subregions. Consistent with these mechanistic insights, animal and human studies demonstrate that reduced GAT3 expression is associated with compulsive alcohol use and impaired reward-related behaviour, reinforcing impaired GABA clearance as a central mechanism in this behavioural shift. Taken together, these lines of evidence validate a central therapeutic model, namely, that targeting altered tonic inhibition and impaired GABA clearance in AUD could address the inhibitory dysfunction that sustains the disorder. Overall, this work supports a unifying model in which receptor adaptations and disrupted GABA removal maintain altered inhibitory tone, driving maladaptive circuit function and contributing to the persistence of AUD.