Abstract
Cannabinoid CB1 receptors are densely expressed on striatal projection neurons expressing dopamine D1 or D2 receptors. However, the specific neuronal distribution of CB1 receptors within the striatum is not known. Previous research has established that the endocannabinoid system controls facilitation of behavior by dopamine D2 receptors, but it is not clear if endocannabinoids also modulate D1 receptor-mediated motor behavior. In the present study, we show that cannabinoid CB1 receptor mRNA is present in striatonigral neurons expressing substance P and dopamine D1 receptors, as well as in striatopallidal neurons expressing enkephalin and dopamine D2 receptors. We explored the functional relevance of the interaction between dopamine D1 and D2 receptors and cannabinoid CB1 receptors with behavioral pharmacology experiments. Potentiation of endogenous cannabinoid signaling by the uptake blocker AM404 blocked dopamine D1 receptor-mediated grooming and 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 D1 receptor-mediated behaviors in addition to its previously described effect on dopamine D2 receptor-mediated behaviors. The effect of AM404 on grooming behavior was absent in dopamine D1 receptor knockout mice, demonstrating its dependence on D1 receptors. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D1 and D2 receptor-mediated behaviors, a finding that may contribute to our understanding of basal ganglia motor disorders.
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Acknowledgements
This work was supported by MEC SAF2003-4864, SAF 2004-07762, C03/06/02/NAC, Delegación del Gobierno para el Plan Nacional Sobre Drogas and FIS (Red temática de Trastornos Adictivos, RD06/0001) CIBERNED to RM, EFE, MN, and FRF; FIS031004 PI 071073 to RM, and FIS040155 and Junta de Andalucia CVI127 to EFE.
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The authors declare that, except for income received from our primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Martín, A., Fernandez-Espejo, E., Ferrer, B. et al. Expression and Function of CB1 Receptor in the Rat Striatum: Localization and Effects on D1 and D2 Dopamine Receptor-Mediated Motor Behaviors. Neuropsychopharmacol 33, 1667–1679 (2008). https://doi.org/10.1038/sj.npp.1301558
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DOI: https://doi.org/10.1038/sj.npp.1301558
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