Ethanol consumption potentiates dopaminergic signaling that is partially mediated by the D 1 dopamine receptor; however, the mechanism(s) underlying ethanol-dependent modulation of D 1 signaling is unclear. We now show that ethanol treatment of D 1 receptor-expressing cells decreases D 1 receptor phosphorylation and concurrently potentiates dopamine-stimulated cAMP accumulation. Protein kinase C (PKC) inhibitors mimic the effects of ethanol on D 1 receptor phosphorylation and dopamine-stimulated cAMP levels in a manner that is non-additive with ethanol treatment. Ethanol was also found to modulate specific PKC activities as demonstrated using in vitro kinase assays where ethanol treatment attenuated the activities of lipid-stimulated PKCg and PKCd in membrane fractions, but did not affect the activities of PKCa, PKCb 1 , or PKCe. Importantly, ethanol treatment potentiated D 1 receptormediated DARPP-32 phosphorylation in rat striatal slices, supporting the notion that ethanol enhances D 1 receptor signaling in vivo. These findings suggest that ethanol inhibits the activities of specific PKC isozymes, resulting in decreased D 1 receptor phosphorylation and enhanced dopaminergic signaling.