Cocaine exerts multiple neurochemical effects in the central nervous system through inhibition of the dopamine transporter at the synapse. Here we report that systemic administration of the drug induces rapid phosphorylation of CREB in the mouse striatum where expression of the nuclear proto-oncogene c-fos is observed. In MPTP-treated mice, in which dopaminergic neurones are degenerated and which show Parkinsonism-like behaviour, however, CREB phosphorylation is not induced by cocaine exposure and c-fos expression is significantly depressed in comparison with controls. These data suggest that CREB may play a major role in the dopaminergic activation of c-fos in the striatum and that the lack of a CREB-induced transcription cascade may have a critical relevance for long-lasting psychomotor disorders in Parkinsonism.