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 D 1 or D 2 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 D 1 - and D 2 -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 D 1 -MSNs and GABAergic transmission in D 2 -MSNs. In vivo chemogenetic excitation of D 1 -MSNs, mimicking glutamatergic strengthening, promoted alcohol consumption; the same effect was induced by D 2 -MSN inhibition, mimicking GABAergic strengthening. Importantly, suppression of GABAergic transmission via D 2 receptor–glycogen synthase kinase–3β signaling dramatically reduced excessive alcohol consumption, as did selective inhibition of D 1 -MSNs or excitation of D 2 -MSNs. Conclusions Our results suggest that repeated cycles of excessive alcohol intake and withdrawal potentiate glutamatergic strength exclusively in D 1 -MSNs and GABAergic strength specifically in D 2 -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.