REGULATION OF BRAIN SEROTONIN RECEPTORS

大脑血清素受体的调节

基本信息

批准号：
3379040
负责人：
Milton Teitler
金额：
$ 13.73万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-12-01 至 1993-11-30
项目状态：
已结题

项目摘要

Altered sensitivity of multiple brain serotonin (5HT) receptors has been hypothesized in the etiology and/or treatment of anxiety, depression, sleep disorders, sexual behaviors, and psychosis. The roles that the multiple 5HT receptor systems play in brain function are still largely unknown, as are the neuronal mechanisms through which 5HT receptors alter cellular function. To better understand the nature of the brain's 5HT receptors have been developed and will be used in conjunction with in vivo manipulations to further our understanding of the role these receptors systems play in brain function and the effects of drugs. a) Preliminary evidence for the existence of a novel brain 5HT receptor, the 5HT1D receptors, has been uncovered. Detailed radioligand binding and adenylate cyclase studies of the 5HT1D receptor will be performed in various mammalian tissues including rat and human brain. b) in order to determine the susceptibility of the 5-HT1D receptors system to sensitivity changes, 5HT transmission in rats will be altered by acute and chronic administration of serotonin neurotoxins, receptor antagonists, agonists, anxiolytics, antidepressants, and electroconvulsive shock. Alterations in the amount of 5-HT1D receptors, the interaction of the 5HT1D receptor with its associated GTP-binding protein, and the coupling between 5HT1D receptors and brain adenylate cyclase activity due to these perturbations will be monitored. c) Preliminary studies have demonstrated that 125I-DOI labels either alternatively, a unique 5HT2 receptor with high affinity for 5HT2 agonists or, alternatively, a unique 5HT2 receptor distinct from that labelled by 3H-ketanserin. In order to address this question the distribution and regulation of the 125I-DOI labelled receptors will be determined and compared with the distribution and regulation of 3H-ketanserin (an antagonist) labelled 5-HT2 receptors in multiple brain regions. d) In order to investigate the role of the brain 5HT1A receptor systems in the actions of antidepressants and novel anxiolytics the affects of these drugs on 3H-BMY 7378 (the first 5HT1A receptor antagonist radioligand), and on the associated 5HT1A receptor-mediated inhibition of adenylate cyclase activity will be monitored.

多个大脑血清素 (5HT) 受体的敏感性改变在焦虑的病因学和/或治疗中被假设，抑郁症、睡眠障碍、性行为和精神病。这多个 5HT 受体系统在大脑功能中发挥的作用仍然很大程度上未知，通过的神经机制也是如此 5HT受体改变细胞功能。为了更好地理解大脑 5HT 受体的性质已经开发出来将与体内操作结合使用以进一步我们对这些受体系统在大脑中发挥的作用的理解药物的功能和作用。 a) 初步证据大脑中存在一种新型 5HT 受体，即 5HT1D 受体被揭露。详细的放射性配体结合和腺苷酸环化酶 5HT1D受体的研究将在不同的领域进行哺乳动物组织，包括大鼠和人脑。 b) 为了确定 5-HT1D 受体系统的敏感性敏感性改变，5HT在大鼠中的传递将被改变血清素神经毒素、受体的急性和慢性给药拮抗剂、激动剂、抗焦虑药、抗抑郁药和电惊厥。 5-HT1D含量的变化受体，5HT1D 受体与其相互作用相关的 GTP 结合蛋白，以及 5HT1D 之间的偶联受体和脑腺苷酸环化酶活性由于这些将监测扰动。 c) 初步研究证明 125I-DOI 标签或者是一个独特的 5HT2受体与5HT2激动剂具有高亲和力，或者，或者，与标记的受体不同的独特 5HT2 受体通过 3H-酮色林。为了解决这个问题 125I-DOI标记受体的分布和调节确定并与分布和调节进行比较 3H-酮色林（一种拮抗剂）在多种中标记 5-HT2 受体大脑区域。 d) 为了研究大脑的作用 5HT1A受体系统在抗抑郁药和新型药物中的作用抗焦虑药这些药物对 3H-BMY 7378（第一个 5HT1A 受体拮抗剂放射性配体），以及相关的 5HT1A 受体介导的腺苷酸环化酶活性抑制被监控。