SIGNALING MECHANISMS IN DOPAMINE RECEPTOR SYNERGISM

多巴胺受体协同作用中的信号机制

• 批准号: 6913402
• 负责人: ASHIWEL S UNDIEH
• 金额: $ 22.28万
• 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/6913402
• 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（由申请人提供）：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。异常多巴胺功能与多种神经和精神疾病的表达或进展相关，包括帕金森病、运动障碍、精神分裂症、药物成瘾和抽动秽语障碍。本研究的长期目标是阐明细胞外多巴胺作用通过细胞膜传递以调节正常或患病大脑中的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样受体的刺激抑制AC活性。然而，这种多巴胺受体功能的传统观点并没有始终如一地解释许多观察结果，即D1样和D2样受体的共激活主要产生协同作用，而不是相反的功能效应。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样受体可以刺激磷酸肌醇（PI）水解独立于AC刺激。 基于这些发现和其他初步数据，我们提出了多巴胺受体协同作用的模型，其中与AC的D2样激动剂抑制和/或细胞内钙动员的促进一致的PI水解的D1样激动剂刺激可以导致细胞或行为水平的协同功能结果。拟议的研究将使用已知的D1样/D2样受体协同作用的行为指标在完整脑内测试该模型的有效性。各种选择性D1样激动剂对体内PI水解的作用将与单独给予或与D2样激动剂喹吡罗联合给予的激动剂的行为效应相关。还将评估特定D2样受体亚型在协同相互作用中的作用。这些结果有望从根本上阐明PI通路在多巴胺能功能中的重要性，特别是因为它可能与D1样/D2样激动剂之间的协同相互作用有关。这些发现还可能对用于各种脑部疾病的多巴胺药物的治疗机制产生新的见解，从而促进未来开发更安全，更有效的药物来治疗或预防这些疾病。