Changes in the level of dopaminergic activity in the rat striatum lead to the induction of a number of immediate-early genes, including c-fos and zif/268. These immediate-early genes are thought in turn to alter the rate of transcription of downstream genes. There is evidence that the dopaminergic activation of the c-fos and zif/268 genes in the striatum in vivo is linked to stimulation of D1-like dopamine receptors. We have used primary cultures of embryonic rat striatal neurons to identify the intracellular pathways involved in this response. Dopamine (10 nM-5 microM) caused a marked increase in the levels of c-fos mRNA and zif/268 mRNA in cultured striatal neurons, an effect that was reproduced by the D1-like dopamine receptor agonist SKF38393 (10 nM-5 microM). These actions were attenuated by the D1-like antagonist SCH23390 (1 microM) but not by the D2-like antagonist eticlopride (1 microM). The D2-like agonist quinpirole did not increase zif/268 mRNA above basal levels at concentrations up to 5 microM, but caused a slight increase in the levels of c-fos mRNA. The stimulation of c-fos mRNA levels caused by 1 microM SKF38393 was reduced by 45% following pretreatment with the selective protein kinase A inhibitor KT5720, and by 87% following pretreatment with the selective protein kinase C inhibitor calphostin C. The stimulation of zif/268 mRNA levels caused by 1 microM SKF38393 was reduced by 90% following pretreatment with KT5720, but was not significantly affected by pretreatment with calphostin C. In addition, the actions of SKF38393 to stimulate the expression of both immediate-early genes were attenuated by coadministration of quinpirole. These results suggest that SKF38393 acts on striatal neurons to stimulate c-fos expression predominantly through protein kinase C, but also partially through protein kinase A. Conversely, SKF38393 induces zif/268 expression through protein kinase A. The ability of quinpirole to antagonize the actions of SKF38393 on cultured neurons is consistent with the presence of both D1-like receptors on the same neuronal population.