BEHAVIORAL & BIOCHEMICAL CORRELATES OF DOPAMINE

行为的

• 批准号: 3563713
• 负责人: BENJAMIN WEISS
• 金额: $ 14.54万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1991-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3563713
• 关键词: 6 hydroxydopamine; acetylcholine; adenylate cyclase; apomorphine; behavior; caudate nucleus; corpus striatum; cyclic AMP; dopamine; drug delivery systems; ergolines; experimental brain lesion; frontal lobe /cortex; high performance liquid chromatography; nucleus accumbens; olfactory lobe; phosphorylation; synapses

The long term objective of this project is to understand the biochemical mechanisms involved in the selective alteration of dopaminergic function. In the present studies we plan to examine the behavioral & biochemical effects of chronically treating mice with selective D1 and D2 agonists. We will determine these effects in normal mice and in mice in which a dopaminergic system has been made supersensitive to dopaminergic agonists. The system used to study altered dopaminergic function is the well characterized model of mice with unilateral lesions of the corpus striatum induced by injecting 6-hydroxdopamine. These lesions result in a supersensitive turning behavior in response to dopamine agonists. Our preliminary studies show that it is possible to reverse this behavioral supersensitivity in mice by the continuous administration of apomorphine or selective dopaminergic agonists. The aims of this proposal are: a) to characterize more fully the effects of these agonists, b) to determine the differential involvement of D1 and D2 dopaminergic systems in dopaminergically mediated behaviors in normal and supersensitive mice and to determine the biochemical correlates of both the dopaminergic supersensitivity and the reversal of this effect induced by the dopamine agonists. Accordingly we will examine the correspondence between altered dopaminergic behavior and: a) the density and properties of postsynaptic D1 and D2 receptors; b) biochemical dopaminergic functions that are coupled to the D1 and D2 receptors--namely, dopamine-stimulated adenylate cyclase activity and inhibition of the release of acetylcholine, respectively; and c) certain post- receptor events that may be responsible for altered dopaminergic function--namely, the activity of calmodulin and the phosphorylation of striatal proteins. The results of these studies should increase our basic understanding of dopaminergic function and ultimately suggest different target sites or novel pharmacotherapies for ameliorating neurologic or psychiatric disorders that involve abnormal dopaminergic activity.

该项目的长期目标是了解 与选择性改变有关的生化机制 多巴胺能功能。 在目前的研究中，我们计划检查 长期治疗小鼠的行为和生化效应 有选择性D1和D2激动剂。 我们将确定这些 在普通小鼠和多巴胺能的小鼠中作用 系统对多巴胺能激动剂的超级敏感。 用于研究改变多巴胺能功能的系统是 具有单侧病变的小鼠模型良好的模型 通过注射6-羟基胺的诱导纹状体。 这些 病变导致对响应的超敏感转折行为 多巴胺激动剂。 我们的初步研究表明这是 可以通过 连续给予磷灰石或选择性 多巴胺能激动剂。 该提议的目的是：a） 更充分地表征这些激动剂的影响，b） 确定D1和D2的差异参与 多巴胺能在多巴胺能介导的行为中的多巴胺能系统 正常和超敏感小鼠，并确定生化 多巴胺能超敏的相关性和 多巴胺激动剂引起的这种作用的逆转。 因此，我们将检查变更之间的对应关系 多巴胺能行为和：a） 突触后D1和D2受体； b）生化多巴胺能 耦合到D1和D2受体的功能 - 即 多巴胺刺激的腺苷酸环化酶活性和抑制 乙酰胆碱的释放； c）某些职位 - 可能导致多巴胺能改变的受体事件 功能 - 即，钙调蛋白的活性和 纹状体蛋白的磷酸化。 这些研究的结果 应该增加我们对多巴胺能功能的基本理解 最终建议不同的目标站点或新颖 改善神经系统或精神病的药物治疗 涉及异常多巴胺能活性的疾病。