In the mammalian fetus, proliferation of the majority of cells destined for the cerebral cortex takes place within the transient proliferative zones of the cerebral wall. Recent investigations have demonstrated that cell of these zones express high levels of D1 dopamine receptors (D1Rs). However, the specific roles of these receptors have not been investigated. The present study tests the hypothesis that D1Rs are capable of regulating the cell cycle of cerebral cortical precursor cells. For this purpose, primary cultures of cells of the proliferative zones from the cerebral wall of 14-day-old mouse fetuses were generated and maintained in the presence of either fibroblast growth factor-2 (FGF2) or epidermal growth factor (EGF). These growth factors were chosen as supporting two distinct populations of precursor cells in the fetal cortical proliferative matrix. The involvement of D1Rs in the regulation of proliferative activity was examined by the addition of a range of concentrations of the D1R-specific agonist, SKF82958, to the culture media. Bromodeoxyuridine incorporation assays demonstrated that exposure to this agonist led to a dose-dependent reduction of DNA synthesis in both FGF2- and EGF-supported cultures. Flow cytometric cell cycle assays further revealed that this was due to prevention of the transition of cells from the G1 phase to the S phase of the cell cycle. The D1R specificity of the effects of SKF82958 was supported in that they were blocked by the addition of the D1R antagonists, SCH23390 or NNC010756. We also found that D1R stimulation induced stronger suppression of proliferative activity in EGF-supported than in FGF2-supported cultures. Our observations suggest that D1Rs are capable of regulating the cell cycle during corticogenesis. Furthermore, they raise a possibility that these receptors may display different efficacies in affecting proliferative activity in FGF2-supported versus EGF-supported cerebral cortical precursor cells.