Dopaminergic drugs increase the expression of the proto-oncogene, c-fos, in the brain, which is involved in the coordination of neurobiological changes caused by repeated cocaine or amphetamine use. This study examined the roles of five dopamine receptor subtypes on the c-fos promoter activity. D1R or D5R significantly increased the expression of c-fos promoter by activating protein kinase A. However, D2R, D3R, or D4R did not show any noticeable effects. The co-expression of D1R/D3R or D1R/D2R synergistically activated the basal and agonist-induced expression of the c-fos promoter, respectively. The Ral guanin&-nucleotide-dissociation-stimulator-like, which was found to interact with the 3rd cytoplasmic loop of D3R, mediated the inhibitory activity of D3R in c-fos expression. In summary, the expression of the c-fos promoter was increased by the D1-like receptors and enhanced synergistically by the D2-like receptors via the modulation of cellular cAMP. D3R inhibited the expression of the c-fos promoter through an interaction with RGL. (c) 2007 Elsevier Inc. All rights reserved.