SIGNALING MECHANISMS IN DOPAMINE RECEPTOR SYNERGISM

多巴胺受体协同作用中的信号机制

• 批准号: 7099398
• 负责人: ASHIWEL S UNDIEH
• 金额: $ 4.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099398
• 关键词: behavior; biological signal transduction; dopamine receptor; hydrolysis; laboratory rat; neuropsychology; phosphatidylinositols; phospholipase C; protein protein interaction; psychopharmacology; receptor binding; receptor expression

DESCRIPTION (provided by applicant): Dopamine plays important roles in the neural regulation of movement, motivation, memory, cognition, mood, and neuroendocrine integration. Abnormal dopamine function is associated with the expression or progression of diverse neurological and psychiatric diseases, including Parkinson disease, dyskinesias, schizophrenia, drug addiction, and Tourette disorder. The long-term objective of this research is to clarify the mechanisms by which extracellular dopamine actions are conveyed across the cell membrane to modulate cellular function and behavior in the normal or diseased brain. It is well known that stimulation of dopamine D1-like receptors is linked to the activation of intracellular adenylate cyclase (AC) activity, whereas stimulation of D2-like receptors inhibits AC activity. This conventional view of dopamine receptor function, however, has not consistently accounted for numerous observations that the coactivation of D1-like and D2-like receptors produces mostly synergistic, rather than oppositional, functional effects. There is compelling evidence, however, that D2-like receptors can mobilize other signaling pathways, including intracellular calcium, independent of AC inhibition, and that D1-like receptors can stimulate phosphoinositide (PI) hydrolysis independent of AC stimulation. Based on these findings and other preliminary data, we have proposed a model of dopamine receptor synergism wherein Dl-like agonist stimulation of PI hydrolysis in consonance with D2-like agonist inhibition of AC and/or facilitation of intracellular calcium mobilization, can lead to synergistic functional outcomes at the cellular or behavioral levels. The proposed research will test the validity of this model within the intact brain using known behavioral indices of D1-like/D2-like receptor synergism. The effects of variously selective D1-like agonists on in vivo PI hydrolysis will be correlated with the behavioral effects of the agonists given alone or in combination with the D2-like agonist quinpirole. The role of specific D2-like receptor subtypes in the synergistic interactions also will be assessed. The results are expected to substantially clarify the significance of the PI pathway in dopaminergic function especially as it may relate to the synergistic interactions among D1-like/D2-like agonists. The findings might also yield new insights into the therapeutic mechanisms of dopamine agents that are used in diverse brain disorders, thus facilitating the future development of safer and more efficacious medications for treating or preventing these diseases.

描述（申请人提供）：多巴胺在运动、动机、记忆、认知、情绪和神经内分泌整合的神经调节中起重要作用。多巴胺功能异常与多种神经和精神疾病的表达或进展有关，包括帕金森病、运动障碍、精神分裂症、药物成瘾和图雷特病。本研究的长期目标是阐明细胞外多巴胺作用在正常或病变大脑中通过细胞膜传递以调节细胞功能和行为的机制。众所周知，多巴胺d1样受体的刺激与细胞内腺苷酸环化酶（AC）活性的激活有关，而d2样受体的刺激则抑制AC活性。然而，这种关于多巴胺受体功能的传统观点并没有一致地解释d1样受体和d2样受体的共同激活主要产生协同作用而不是对立作用的大量观察结果。然而，有令人信服的证据表明，d2样受体可以动员其他信号通路，包括细胞内钙，独立于AC抑制，d1样受体可以独立于AC刺激刺激磷酸肌苷（PI）水解。