Behavioral and molecular studies have established a link between drugs of abuse and the central melanocortin system, particularly the melanocortin 4 receptor (MC4-R). The present study expands this line of investigation to characterization of the neurochemical and behavioral interactions between MC4-R and the psychomotor stimulant, cocaine. The results demonstrate that repeated, but not acute, cocaine administration up-regulates MC4-R mRNA expression in the striatum and hippocampus, but not cerebral cortex. Pharmacological studies indicate that the up-regulation of MC4-R expression occurs via dopamine D1 and D2 receptor-dependent mechanisms. The D1/D2 antagonist haloperidol and the D2-selective antagonist eticlopride mimic the effect of cocaine on MC4-R expression. In addition, coadministration of a D1-selective antagonist, SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], completely blocks the up-regulation of MC4 mRNA by cocaine, demonstrating that D1 receptor activation is necessary for this response. Moreover, the results demonstrate that cocaine treatment increases behavioral responses (grooming and locomotor activity) to infusions of a melanocortin agonist, indicating that up-regulation of MC4-R expression results in functional consequences. These data further support a role for the melanocortin-MC4-R neuropeptide system in the biochemical and behavioral effects of cocaine.