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)在精神疾病的表达中起着关键作用 精神分裂症的症状。同样，检察官似乎也参与了 Tourette和Lesch等发育障碍的病理生理学研究 尼汉综合征，以及伴有多动症的注意力缺陷障碍。 DA的生理作用是通过它与D1的相互作用来实现的 和D2受体(尽管D3、D4和D5受体被认为是 用分子生物学方法论鉴定)。因为D1受体 自身调节行为，以及影响D2的表达 受体介导的行为、D1受体表达的变化和 活动可能在精神障碍的病理生理学中起重要作用 DA神经传递，如精神分裂症和多发性抽动症。一 这项研究计划的长期目标是更好地了解D1 正常受试者的受体功能和可塑性 发育过程中的多巴胺能活动。两种分子的结果 生物学和行为学研究表明，不止一个D1受体 子类型存在。目前，这些工具还无法证明 生化上有两种不同的d1亚型，作为选择性药物 因为这些假定的亚型并不存在。初步结果表明， 可能有两个D1受体系统受到不同的影响 在发育过程中的不同时期消耗DA。因此，可能有两个 独立发育的D1受体系统，并可能 与其他受体系统以不同方式相互作用。五花八门 将利用药物干预来改变这种相互作用 在发育过程中DA与其受体之间的相互作用。该组织和 将分析发展议程系统的各个组成部分的数量 定量受体放射自显影和免疫细胞化学。一部经典的 将使用行为药理学的方法来研究功能 D_1受体的可塑性(S)及其与D_2受体的相互作用 以及中枢神经系统内的5-羟色胺受体。通过 使用选择性激动剂和拮抗剂的组合治疗DA和 5-羟色胺受体，行为方法将被用来检测 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， D1R通过促进D2受体的活性 和抑制相互作用。这两种类型的交互， 调节不同的DA介导的行为，可能通过两种方式调节 不同亚型的D1R。补充约束性研究将是 通过定量受体放射自显影进行，这允许 受体的定量和离散定位 利息。更清楚地了解哪些子类型介导了特定的 精神运动效应将促进更具体药物的开发和 从而改善涉及DA异常的疾病的治疗 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.