CB1 receptor agonists increase the state of phosphorylation of the dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at the cAMP-dependent protein kinase site, Thr 34. This effect, which occurs in the medium spiny neurons of the striatum, has been proposed to mediate the motor depressant action of cannabinoids. In this study, we have examined the effect produced by systemic administration of Delta(9)-tetrahydrocannabinol (THC), the major component of marihuana and hashish, on DARPP-32. We show that THC increases DARPP-32 phosphorylation at Thr 34 both in dorsal striatum and nucleus accumbens. Time-course and dose-response experiments indicate that DARPP-32 phosphorylation is maximal 30 min following administration of 10mg/kg of THC. The THC-mediated increase in DARPP-32 phosphorylation is reduced by administration of the CB1 receptor antagonist, SR141716A (3mg/kg). A similar attenuation of the effect of THC is also exerted by suppression of cAMP signaling achieved using the dopamine D1 receptor antagonist, SCH23390 (0.125 mg/kg), or the adenosine A2A receptor antagonist, KW6002 (3mg/kg). These results indicate that, in the striatum, THC promotes PKA-dependent phosphorylation of DARPP-32 in striatal medium spiny neurons expressing dopamine D1 and adenosine A2A receptors.