Cannabinoid CB1 receptors are densely expressed on striatal projection neurons expressing dopamine D1 or D2 receptors, but the specific neuronal distribution of CB1 receptors within the striatum is not known. The endocannabinoid system controls facilitation of behavior by dopamine D2 receptors, but the role of dopamine D1 receptors on motor behavior is not clear. In the present study we show through in situ hybridization that cannabinoid CB1 receptors are present in striatonigral neurons expressing substance P and dopamine D1 receptors, as well as in striatopallidal neurons expressing dopamine D2 receptors. The expression of CB1 receptors is higher in striatonigral neurons. We explored the functional relevance of the interaction between dopamine D1 and D2 and cannabinoid CB1 receptors. Potentiation of endogenous anandamide by AM404 blocked dopamine D1 receptor-mediated grooming as well as D2 receptor-mediated oral stereotypies. In addition, contralateral turning induced by unilateral intrastriatal infusion of D1 receptor agonists is counteracted by AM404 and potentiated by the cannabinoid antagonist SR141716A. These results indicate that the endocannabinoid system negatively modulates not only dopamine D2 receptor-mediated responses, as initially described, but also D1 receptor-mediated behaviors. The effect of AM404 on grooming behavior was dependent on D1 receptors as we did not observe this opposite effect in dopamine D1 receptor knockout mice. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D1 and D2 receptor-mediated behaviors.

Supported by MEC 04-07762, SAF2003-4864, PNSD and FIS (Trastornos Adictivos, G03/05, C03/06/02/NAC) to RM, EFE, MN and FRF.