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

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.

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.

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.

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.