Repeated exposure to cocaine induces persistent neuroadaptations that involve alterations in cellular signaling and gene expression mediated by dopamine (DA) receptors in the brain. Both dopamine D1 and D3 receptors mediate cocaine-induced behaviors and they are also coexpressed in the same neurons in the nucleus accumbens (NAc) and caudoputamen (CPu). We have investigated whether these two receptors coordinately regulate intracellular signaling and gene expression after acute and repeated cocaine administration. We found that extracellular signal-regulated kinase (ERK) activation and c-fos induction in the CPu following an acute cocaine administration is mediated by the D1 receptor and inhibited by the D3 receptor. ERK activation is necessary for acute cocaine-induced expression of fos family genes that include c-fos, fosB, and fra2. Furthermore, potential target genes of cAMP response element-binding (CREB) protein and/or AP-1 transcription complex, including dynorphin, neogenin, and synaptotagmin VII, are also oppositely regulated by D1 and D3 receptors after repeated cocaine injections. Lastly, such regulation requires proper ERK activation. These results suggest that D1 and D3 receptors oppositely regulate target gene expression by regulating ERK activation after cocaine administration. © 2006 New York Academy of Sciences.