DREADDs defining ETOH actions on striatal D1 and D2 pathways

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


In this study, we measured both glutamatergic and GABAergic activity in D1-MSNs and D2-MSNs and found that NMDA receptor (NMDAR) activity in D1-MSNs and GABAergic activity in D2-MSNs were selectively potentiated following cycles of alcohol consumption and withdrawal. Using a chemogenetic approach employing designer receptors exclusively activated by designer drugs (DREADDs), which allowed selective manipulation of D1- or D2-MSN activity (23), we discovered that both of these cell types were not only necessary, but also sufficient, to drive alcohol consumption. Furthermore, we observed that D2R-glycogen synthase kinase-3β (GSK3β) signaling regulated GABAergic activity and thus, alcohol consumption. The findings of this study provide detailed mechanistic information indicating how different forms of neuroplasticity in distinct neuronal populations of the striatal direct and indirect pathways drive alcohol consumption.

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