Dopamine D1 and D3 Receptors Are Differentially Involved in Cocaine-Induced Reward Learning and Cell Signaling

Memories of learned associations between the rewarding properties of drugs and environmental cues contribute significantly to craving and relapse in humans. We have investigated how dopamine (DA) D1 and D3 receptors modulate the acquisition and extinction of cocaine-induced reward learning and associated changes in cellular signaling in reward circuits in the brain. We found that D1 receptor mutant mice failed to acquire conditioned place preference (CPP) compared to wild-type mice over a range of cocaine doses. By contrast, D3 receptor mutant mice exhibited potentiated acquisition of CPP compared to wild-type mice at low but not high doses of cocaine. Activation of the extracellular signal-regulated kinase (ERK), but not the c-Jun N-terminal kinase and p38 in the nucleus accumbens, amygdala, and prefrontal cortex was attenuated in D1 receptor mutant mice and potentiated in D3 receptor mutant mice compared to wild-type mice following CPP acquisition. D3 receptor mutant mice also exhibited delayed CPP extinction and sustained ERK activation compared to wild-type mice following extinction training. Our results suggest that D1 and D3 receptors differentially contribute cocaine-induced reward learning by regulating, at least in part, ERK activation in reward circuits in the brain.