Alcohol intake enhances glutamatergic transmission from D2 receptor-expressing afferents onto D1 receptor-expressing medium spiny neurons in the dorsomedial striatum.

Dopaminergic modulation of corticostriatal transmission is critically involved in reward-driven behaviors. This modulation is mainly mediated by dopamine D1 receptors (D1Rs) and D2Rs, which are highly expressed in medium spiny neurons (MSNs) of the dorsomedial striatum (DMS), a brain region essential for goal-directed behaviors and addiction. D1Rs and D2Rs are also present at presynaptic cortical terminals within the DMS. However, it is not known how addictive substances alter the glutamatergic strength of striatal synapses expressing presynaptic dopamine receptors. Using cell type-specific Cre mice in combination with optogenetic techniques, we measured glutamatergic transmission at D1R- or D2R-expressing afferents to DMS MSNs. We found larger excitatory postsynaptic currents at the synapses between the extra-striatal D2R-expressing afferents and D1R-expressing MSNs (D2→D1), as compared with those observed at the other tested synapses (D1→D1, D1→D2, and D2→D2). Additionally, excessive alcohol consumption induced a long-lasting potentiation of glutamatergic transmission at the corticostriatal D2→D1 synapse. Furthermore, we demonstrated that activation of postsynaptic, but not presynaptic, D2Rs inhibited corticostriatal transmission in an endocannabinoid-dependent manner. Taken together, these data provide detailed information on the mechanisms underlying dopamine receptor-mediated modulation of brain reward circuitry.