FUNCTIONAL PLASTICITY OF THE DOPAMINE D1 RECEPTOR

过去30年的大量研究提供了强有力的证据， 多巴胺（DA）在精神分裂症的表达中起着关键作用， 精神分裂症的症状同样，DA似乎参与了 发展障碍的病理生理学，如图雷特和莱施， Nyhan Syndrome，以及多动症。 DA的生理作用是通过与D1的相互作用来介导的 和D2受体（尽管D3，D4和D5受体已经被广泛应用于 用分子生物学方法鉴定）。因为D1受体 调节自身的行为，以及影响D2的表达 受体介导的行为，D1受体表达的改变， 活动可能在疾病的病理生理学中起重要作用， DA神经传递，如精神分裂症和抽动秽语综合征。一 这项研究计划的长期目标是更好地了解D1 受体功能和可塑性的破坏后，正常的 在发育过程中的多巴胺能活性。两种分子的结果 生物学和行为学研究表明， 子类型存在。目前，这些工具还不能证明 从生物化学上讲，有两种不同的D1亚型， 这些假定的亚型并不存在。初步结果表明 可能有两个D1受体系统，它们受到不同的影响， 在发育过程中的不同时间消耗DA。因此，可能有两个 D1受体系统是独立发展的， 与其他受体系统有差异的相互作用。各种 将利用药物干预来改变相互作用 多巴胺和它的受体之间的联系本组织和 将分析DA系统的各种组件的数量， 定量受体放射自显影和免疫细胞化学。一个经典 行为药理学方法将用于研究功能 D1受体的可塑性以及它们如何与D2受体相互作用， 以及中枢神经系统内的血清素受体。通过 使用DA的选择性激动剂和拮抗剂的组合， 5-羟色胺受体，行为方法将用于测试 存在一种以上的D1受体亚型，并确定它们在 DA功能的调节。例如，有证据表明， D1受体通过两种易化作用调节D2受体活性， 和抑制性相互作用。这两种类型的相互作用， 调节不同的DA介导的行为，可以通过两个调节 D1受体的不同亚型。补充结合研究将 进行定量受体放射自显影，这使得 受体的定量和离散定位 兴趣更清楚地了解哪些亚型介导特定的 精神运动效应将促进更具体药物的开发， 从而改善涉及异常DA的疾病的治疗 神经传递

Considerable research over the past 30 years has provided strong evidence that dopamine (DA) plays a pivotal role in the expression of psychotic symptoms in schizophrenia. Similarly, DA appears to be involved in the pathophysiology of such developmental disorders as Tourette and Lesch- Nyhan Syndromes, as well as attention deficit disorder with hyperactivity. The physiological actions of DA are mediated by its interaction with D1 and D2 receptors (although D3, D4 and D5 receptors have putatively been identified with molecular biology methodology). Because D1 receptors mediate behavior on their own, as well as affecting the expression of D2 receptor-mediated behaviors, alterations of D1 receptor expression and activity may play important roles in the pathophysiology of disorders of DA neurotransmission such as schizophrenia and Tourette Syndrome. One long-term objective of this research program is to better understand D1 receptor function and plasticity following disruptions of normal dopaminergic activity during development. Results of both molecular biology and behavioral studies suggest that more than one D1 receptor subtype exists. Currently, the tools are not available to prove biochemically that there are two separate D1 subtypes, as selective drugs for these putative subtypes do not exist. Preliminary results suggest that there may be two D1 receptor systems which are differentially affected by depleting DA at different times during development. Thus, there may be two D1 receptor systems which develop independently and could possibly interact differentially with other receptor systems. Various pharmacological interventions will be utilized to alter the interaction between DA and its receptors during development. The organization and number of the various components of the DA system will be analyzed with quantitative receptor autoradiography and immunocytochemistry. A classical behavioral pharmacology approach will be used to study the functional plasticity of the D1 receptor(s) and how they interact with D2 receptors, as well as serotonin receptors, within the central nervous system. By using combinations of selective agonists and antagonists for DA and serotonin receptors, behavioral methods will be used to test for the presence of more than one D1 receptor subtype and determine their roles in the regulation of DA function. For example, there is evidence to suggest that D1 receptors modulate D2 receptor activity through both facilitatory and inhibitory interactions. These two types of interactions, which modulate distinct DA-mediated behaviors, may be regulated through two distinct subtypes of D1 receptors. Complementary binding studies will be carried out with quantitative receptor autoradiography, which allows for both quantification and discrete localization of the receptors of interest. A clearer understanding of which subtypes mediate particular psychomotor effects would promote development of more specific drugs and thus improve treatment of disorders involving abnormal DA neurotransmission.