Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada, Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy, Skolkovo Institute of Science and Technology, Skolkovo, Moscow Region, 143025, Russia, Faculty of Biology and Soil Science, St. Petersburg State University, St. Petersburg 199034, Russia, and Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University and Institut Universitaire en Santé Mentale de Québec, Québec City, Québec G1J 2G3, Canada.
J Neurosci. 2013 Nov 13;33(46):18125-33. doi: 10.1523/JNEUROSCI.2382-13.2013.
Several studies have reported the coupling of dopamine signaling to phospholipase C β (PLCβ) both in vitro and in vivo. However, the precise physiological relevance of this signaling pathway in mediating dopamine behaviors is still unclear. Here we report that stimulation of dopamine receptor signaling in vivo with systemic administration of apomorphine, amphetamine, and cocaine leads to increased production of inositol triphosphate (IP3) in the mouse striatum. Using selective antagonists and dopamine D1 and D2 receptor knock-out animals, we show that the production of IP3 is mediated by the D1 receptor, but not the D2 receptor. A selective blocker of PLCβ, U73122, was used to assess the physiological relevance of D1-mediated IP3 production. We show that U73122 inhibits the locomotor-stimulating effects of apomorphine, amphetamine, cocaine, and SKF81297. Furthermore, U73122 also suppresses the spontaneous hyperactivity exhibited by dopamine transporter knock-out mice. Importantly, the effects of U73122 are selective to dopamine-mediated hyperactivity, as this compound does not affect hyperactivity induced by the glutamate NMDA receptor antagonist MK801. Finally, we present evidence showing that an imbalance of D1- and D2-mediated signaling following U73122 treatment modifies the locomotor output of animals from horizontal locomotor activity to vertical activity, further highlighting the importance of the PLCβ pathway in the regulation of forward locomotion via dopamine receptors.
已有几项研究报道了多巴胺信号与磷酯酶 Cβ（PLCβ）在体外和体内的偶联。然而，这种信号通路在介导多巴胺行为方面的确切生理相关性尚不清楚。在这里，我们报告说，用阿扑吗啡、安非他命和可卡因全身给药刺激多巴胺受体信号，会导致小鼠纹状体中三磷酸肌醇（IP3）的产生增加。使用选择性拮抗剂和多巴胺 D1 和 D2 受体敲除动物，我们表明 IP3 的产生是由 D1 受体介导的，而不是 D2 受体。我们使用 PLCβ 的选择性阻断剂 U73122 来评估 D1 介导的 IP3 产生的生理相关性。我们表明 U73122 抑制了阿扑吗啡、安非他命、可卡因和 SKF81297 的运动刺激作用。此外，U73122 还抑制了多巴胺转运体敲除小鼠表现出的自发过度活跃。重要的是，U73122 的作用是选择性的，只针对多巴胺介导的过度活跃，因为这种化合物不会影响 NMDA 受体拮抗剂 MK801 诱导的过度活跃。最后，我们提供了证据表明，U73122 处理后 D1 和 D2 介导的信号失衡会改变动物的运动输出，从水平运动活动转变为垂直运动活动，进一步强调了 PLCβ 途径在通过多巴胺受体调节向前运动中的重要性。
