SIGNALING MECHANISMS IN DOPAMINE RECEPTOR SYNERGISM

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发挥重要作用。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、药物成瘾和抽动障碍。这项研究的长期目标是阐明细胞外多巴胺通过细胞膜传递的机制，以调节正常或疾病大脑中的细胞功能和行为。众所周知，刺激多巴胺D1样受体与激活细胞内腺苷环化酶(AC)活性有关，而刺激D2样受体则抑制AC活性。然而，这种对多巴胺受体功能的传统观点并不能一致地解释许多观察结果，即D1样和D2样受体的共同激活主要产生协同作用，而不是对立的功能效应。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，而不依赖AC的抑制；D1样受体可以刺激磷脂酰肌醇(PI)的水解，而不依赖AC的刺激。 基于这些发现和其他初步数据，我们提出了一个多巴胺受体协同作用的模型，在该模型中，D1样激动剂刺激PI的水解，同时D2样激动剂抑制AC和/或促进细胞内钙动员，可以在细胞或行为水平上导致协同功能结果。这项拟议的研究将在完整的大脑中使用已知的D1样/D2样受体协同作用的行为指标来测试该模型的有效性。不同选择性的D1样激动剂对体内PI水解的影响将与激动剂单独或与D2样激动剂奎比罗联合使用的行为效应相关。还将评估特定的D2样受体亚型在协同作用中的作用。这些结果有望在很大程度上阐明PI通路在多巴胺能功能中的意义，特别是因为它可能与D1样/D2样激动剂之间的协同作用有关。这些发现还可能对用于各种脑部疾病的多巴胺制剂的治疗机制提供新的见解，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。

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.