Zhen Xuechu, Goswami Satindra, Friedman Eitan
Department of Physiology/Pharmacology, City University of New York Medical School, 138th Street and Convent Ave. New York, NY 10031, USA.
Pharmacol Biochem Behav. 2005 Apr;80(4):597-601. doi: 10.1016/j.pbb.2005.01.016.
SKF83959, previously described as an antagonist of the D1 dopamine receptor, has been shown to be a potent anti-parkinsonian agent. However, its mechanism of action is unknown. The present communication was designed to study the mechanism by which SKF83959 exerts its pharmacological effects. SKF83959 induced contralateral rotations in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease (PD). The rotations were completely blocked by the D1 dopamine receptor antagonist, SCH23390. The response was not affected by the serotonin receptor antagonist, mesulergine and was transiently attenuated by alpha1 adrenergic or D2 dopamine receptor antagonists, prazosin or spiperone, respectively. Injection of 0.5 and 1 mg/kg SKF83959 elicited significant elevations in IP3 accumulation in lesioned as compared to intact striata. This effect was blocked by SCH23390 at a dose that completely obviated the rotational response to SKF83959, suggesting that activation of the PI-linked D1 dopamine receptor and the PLC/IP3 pathway may be the underlying mechanism for the rotational activity induced by SKF83959. The present data provide the first evidence that the PI-linked D1 dopamine receptor plays a role in regulating motor activity in striatum and that modulation of the D1 dopamine receptor/PLC/IP3 pathway may be a novel target in the discovery of drugs for the treatment of Parkinson's disease.
SKF83959，先前被描述为D1多巴胺受体拮抗剂，已被证明是一种有效的抗帕金森病药物。然而，其作用机制尚不清楚。本通讯旨在研究SKF83959发挥其药理作用的机制。SKF83959在帕金森病（PD）单侧6-OHDA损伤大鼠模型中诱导对侧旋转。这种旋转完全被D1多巴胺受体拮抗剂SCH23390阻断。该反应不受5-羟色胺受体拮抗剂美舒麦角的影响，分别被α1肾上腺素能或D2多巴胺受体拮抗剂哌唑嗪或螺哌隆短暂减弱。与完整纹状体相比，注射0.5和1mg/kg的SKF83959可使损伤纹状体中的IP3积累显著升高。这种效应在完全消除对SKF83959旋转反应的剂量下被SCH23390阻断，这表明PI连接的D1多巴胺受体和PLC/IP3途径的激活可能是SKF83959诱导旋转活动的潜在机制。目前的数据首次证明PI连接的D1多巴胺受体在调节纹状体运动活动中起作用，并且调节D1多巴胺受体/PLC/IP3途径可能是发现治疗帕金森病药物的新靶点。
