DOPAMINE RECEPTOR SUBTYPES AND FUNCTION

多巴胺受体亚型和功能

• 批准号: 3405187
• 负责人: EMANUEL MELLER
• 金额: $ 11.66万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1989-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3405187
• 关键词: SCH 23390; adrenergic agents; antiadrenergic agents; antidepressants; attention deficit disorder; behavioral medicine; brain metabolism; corpus striatum; dopamine; dopamine receptor; drug administration routes; drug interactions; gamma aminobutyrate; laboratory mouse; laboratory rat; microinjections; neuropharmacology; radiotracer; scopolamine; stereotaxic techniques; substantia nigra; SCH 23390; adrenergic agents; antiadrenergic agents; antidepressants; attention deficit disorder; behavioral medicine; brain metabolism; corpus striatum; dopamine; dopamine receptor; drug administration routes; drug interactions; gamma aminobutyrate; laboratory mouse; laboratory rat; microinjections; neuropharmacology; radiotracer; scopolamine; stereotaxic techniques; substantia nigra

In animal models, striatal dopamine (DA) appears to mediate a number of behavioral phenomena, including stereotypy, rotation and catalepsy. At least two distinct DA receptor subtypes (D1 and D2) appear to exist in the mammalian central nervous system. The objective is to gain an understanding of the underlying mechanism(s) involved in the apparent functional interaction between thee receptor subtypes. The specific aims are to provide evidence for the following hypothesis: 1) both D1 and D2 receptors mediate certain behaviors under control by DA; 2) activation of striatonigral systems controlled by these receptors results in convergent functional output, i.e., the response elicited from simultaneous activation of both systems is greater than from either one singly; and 3) these receptors act independently of each other in controlling these functional outputs. Both behavioral and biochemical methods will be utilized to achieve these goals. Advantage will be taken of newer agents possessing demonstrated selectivity of action at these receptor subtypes, e.g.: SKF 38393, LY 171555 (selective D1 and D2 agonists, respectively), SCH 23390 and sulpiride (selective D1 and D2 antagonists, respectively). The hypothesis of convergent D1 and D2 receptor mediation of function will be tested by examining the effects elicited by selective agents singly and in combination on stereotypy (after systemic administration) and on rotation in intact animals (after unilateral intrastriatal application). The hypothesis that separate striatonigral neural systems are under independent control of D1 and D2 receptors will be tested by examining drug/receptor specificity with regard to the effects of intrastriatally applied drugs on GABA turnover in substantia nigra. In ancillary studies selective lesion of D1 or D2 receptors in vivo with the inactivating agent EEDQ will be evaluated for its potential as a new model to assess the functional relationship between D1 and D2 receptors. The insights gained from these basic studies are expected to further our understanding of dopaminergic systems, and therefore of neuropsychiatric disorders in which this neurotransmitter is either demonstrably or putatively involved (e.g. Parkinson's disease and schizophrenia, respectively). Furthermore, the results may lead to fruitful new strategies for treatment of these and related disorders.

在动物模型中，纹状体多巴胺（DA）似乎介导了许多 行为现象，包括刻板印象，旋转和蠕虫病。 在 至少两个不同的DA受体亚型（D1和D2）似乎存在于 哺乳动物中枢神经系统。 目的是获得 了解明显的基本机制 The受体亚型之间的功能相互作用。 具体目标 提供以下假设的证据：1）D1和D2 受体介导DA控制的某些行为； 2）激活 由这些受体控制的纹状体系统导致收敛 功能输出，即同时激活引起的响应 这两个系统的中都大于一个单独的系统。 3）这些 受体在控制这些功能方面彼此独立起作用 输出。 行为和生化方法都将用于 实现这些目标。 拥有拥有的新代理人的优势 在这些受体亚型上表现出作用的选择性，例如：SKF 38393，LY 171555（分别选择性D1和D2激动剂），SCH 23390 和硫磺（分别选择性D1和D2拮抗剂）。 这 收敛D1和D2受体介导的假设将是 通过检查选择性剂并在 刻板印象（全身给药后）和旋转的组合 在完整的动物中（单侧纹状体内应用后）。 这 单独的纹状体神经系统受到独立的假设 D1和D2受体的控制将通过检查药物/受体测试 关于纹状体内施用药物对的特异性 尼格拉岛的GABA营业额。 在辅助研究中，选择性病变 带有灭活剂EEDQ的体内D1或D2受体的摄入 评估其作为评估功能的新模型的潜力 D1和D2受体之间的关系。 从这些中获得的见解 希望基础研究能够进一步了解多巴胺能 系统，因此是神经精神疾病的系统 神经递质是明显的或推测的（例如 帕金森氏病和精神分裂症）。 此外， 结果可能会导致对这些治疗的富有成果的新策略 相关疾病。