Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption

Background: Repeated exposure to addictive drugs or alcohol triggers glutamatergic and gamma-aminobutyric acidergic (GABAergic) plasticity in many neuronal populations. The dorsomedial striatum (DMS), a brain region critically involved in addiction, contains medium spiny neurons (MSNs) expressing dopamine D₁ or D₂ receptors, which form direct and indirect pathways, respectively. It is unclear how alcohol-evoked plasticity in the DMS contributes to alcohol consumption in a cell type-specific manner.

Methods: Mice were trained to consume alcohol using an intermittent-access two-bottle-choice drinking procedure. Slice electrophysiology was used to measure glutamatergic and GABAergic strength in DMS D₁- and D₂-MSNs of alcohol-drinking mice and control mice. In vivo chemogenetic and pharmacologic approaches were employed to manipulate MSN activity, and their consequences on alcohol consumption were measured.

Results: Repeated cycles of alcohol consumption and withdrawal in mice strengthened glutamatergic transmission in D₁-MSNs and GABAergic transmission in D₂-MSNs. In vivo chemogenetic excitation of D₁-MSNs, mimicking glutamatergic strengthening, promoted alcohol consumption; the same effect was induced by D₂-MSN inhibition, mimicking GABAergic strengthening. Importantly, suppression of GABAergic transmission via D₂ receptor-glycogen synthase kinase-3β signaling dramatically reduced excessive alcohol consumption, as did selective inhibition of D₁-MSNs or excitation of D₂-MSNs.

Conclusions: Our results suggest that repeated cycles of excessive alcohol intake and withdrawal potentiate glutamatergic strength exclusively in D₁-MSNs and GABAergic strength specifically in D₂-MSNs of the DMS, which concurrently contribute to alcohol consumption. These results provide insight into the synaptic and cell type-specific mechanisms underlying alcohol addiction and identify targets for the development of new therapeutic approaches to alcohol abuse.