DOPAMINE RECEPTOR SUBTYPES AND FUNCTION

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、旋转和僵硬。 在 至少有两种不同的DA受体亚型（D1和D2）似乎存在于 哺乳动物中枢神经系统 目标是获得一个 了解表面上的 受体亚型之间的功能相互作用。 具体目标 为以下假设提供证据：1）D1和D2 受体在DA的控制下介导某些行为; 2）激活 由这些受体控制的纹状体黑质系统导致会聚 功能输出，即，同时激活引起的反应 这两个系统都大于任何一个单独的;和3）这些 受体相互独立地控制这些功能 产出 行为和生物化学方法将被用来 实现这些目标。 新的代理人拥有的优势将被利用 对这些受体亚型表现出选择性作用，例如： SKF 38393、LY 171555（分别为选择性D1和D2激动剂）、SCH 23390 和舒必利（分别为选择性D1和D2拮抗剂）。 的 会聚D1和D2受体介导功能假说将 通过检查选择性试剂单独和在 刻板（全身给药后）和旋转联合给药 在完整动物中（单侧纹状体内应用后）。 的 分离的纹状体黑质神经系统处于独立状态的假设 将通过检查药物/受体来检测D1和D2受体的控制 关于纹状体内应用药物对 黑质GABA周转。 在辅助研究中，选择性病变 D1或D2受体在体内与灭活剂EEDQ的作用将是 评估其作为评估功能性 D1和D2受体的关系。 从中获得的见解 基础研究有望进一步加深我们对多巴胺能神经元的理解， 系统，因此，神经精神疾病，其中， 神经递质明显或不明显参与（例如， 帕金森病和精神分裂症）。 而且 结果可能导致富有成效的新的战略，为治疗这些和 相关疾病。

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.