Repeated exposure to cocaine can induce neuroadaptations in the brain. One mechanism by which persistent changes occur involves alterations in gene expression mediated by the dopamine receptors. Both the dopamine D1 and D3 receptors have been shown to mediate gene expression changes. Moreover, the D1 and D3 receptors are also coexpressed in the same neurons, particularly in the nucleus accumbens and also caudoputamen (CPu). Little is known however, whether these two receptors coordinately regulate gene expression after cocaine administration and the underlying mechanisms. We have used various gene mutant mice to address this issue. We show that extracellular signal-regulated kinase (ERK) activation and c-fos induction in the CPu in response to acute cocaine administration is mediated by the D1 receptor and inhibited by the D3 receptor. Moreover, ERK activation mediates acute cocaine-induced expression of Fos family genes, including c-fos, fosB and fra2. Interestingly, dynorphin, neogenin, and synaptotagmin VII, genes that possess cAMP-response element binding protein and AP-1 transcription complex-binding consensus sequences in their promoters, are also oppositely regulated by the D1 and D3 receptors after repeated exposure to cocaine. Furthermore, such regulation depends on proper ERK activation and c-fos function. These results suggest that the D1 and D3 receptors elicit opposite regulation of target gene expression by regulating ERK activation and c-fos induction after acute and chronic cocaine treatment.