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

Abstract 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.