Martín Ana Belén, Fernandez-Espejo Emilio, Ferrer Belén, Gorriti Miguel Angel, Bilbao Ainhoa, Navarro Miguel, Rodriguez de Fonseca Fernando, Moratalla Rosario
Instituto Cajal, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
Neuropsychopharmacology. 2008 Jun;33(7):1667-79. doi: 10.1038/sj.npp.1301558. Epub 2007 Oct 24.
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.
大麻素CB1受体在表达多巴胺D1或D2受体的纹状体投射神经元上高度表达。然而,CB1受体在纹状体内的具体神经元分布尚不清楚。先前的研究已证实内源性大麻素系统通过多巴胺D2受体控制行为的促进作用,但内源性大麻素是否也调节D1受体介导的运动行为尚不清楚。在本研究中,我们发现大麻素CB1受体mRNA存在于表达P物质和多巴胺D1受体的纹状体黑质神经元中,以及表达脑啡肽和多巴胺D2受体的纹状体苍白球神经元中。我们通过行为药理学实验探讨了多巴胺D1和D2受体与大麻素CB1受体之间相互作用的功能相关性。摄取阻断剂AM404增强内源性大麻素信号传导,可阻断多巴胺D1受体介导的梳理行为和D2受体介导的口部刻板行为。此外,单侧纹状体内注射D1受体激动剂诱导的对侧旋转可被AM404抵消,并被大麻素拮抗剂SR141716A增强。这些结果表明,内源性大麻素系统除了对多巴胺D2受体介导的行为有先前描述的作用外,还对D1受体介导的行为产生负调节作用。AM404对梳理行为的影响在多巴胺D1受体基因敲除小鼠中不存在,表明其对D1受体的依赖性。本研究表明,内源性大麻素系统是多巴胺D1和D2受体介导行为的相关负调节因子,这一发现可能有助于我们理解基底神经节运动障碍。