SEROTONIN REUPTAKE INHIBITORS AND 5HT 1A RECEPTORS

5-羟色胺再摄取抑制剂和 5HT 1A 受体

• 批准号: 6539826
• 负责人: LOUIS D VAN DE KAR
• 金额: $ 28.7万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6539826
• 关键词: G protein; antisense nucleic acid; autoradiography; dendrites; dietary aminoacid; dietary restriction; fluoxetine; hypothalamus; laboratory rat; neuroendocrine system; neuropharmacology; nutrition related tag; receptor sensitivity; serotonin inhibitor; serotonin receptor; synapses; tryptophan; western blottings

DESCRIPTION: (Adapted from applicant's abstract) This project focuses on the pharmacology of brain serotonin (5-HT) neurons after chronic exposure to 5-HT uptake blockers. Impaired function of 5-HT1A receptors has been associated with neurological and psychiatric disorders. Chronic exposure to 5-HT uptake blockers reduces 5-HT1A receptor function of serotonergic cells in the midbrain. However, little information is currently available regarding the effect of 5-HT uptake blockers on hypothalamic post-synaptic 5-HT1A receptors. Moreover, no studies have investigated such fundamental issues as the time- course, dose-response relationship or duration of the effects of 5-HT uptake blockers on 5- HT1A receptor function. The applicant has recently found that the 5-HT uptake blocker fluoxetine (10 mg/kg/day, 21 days) reduces 5-HT1A receptor-mediated plasma ACTH and oxytocin responses in a time-dependent manner. A single injection of fluoxetine had no effect. The hypothesis is advanced that chronic exposure to 5-HT uptake blockers causes adaptational changes in serotonergic neurotransmission, resulting in reduced 5-HT1A receptor function in the hypothalamus. The proposed studies will characterize the changes in hypothalamic post-synaptic 5- HT1A receptors induced by chronic exposure to 5-HT uptake blockers. Biochemical approaches will focus on changes in 5-HT1A receptor density and their signal transduction mechanisms (coupling to G-proteins). In addition, the responsiveness of hypothalamic 5-HT1A receptors will be determined from the neuroendocrine responses to specific 5- HT1A agonists. Specific Aim 1 will investigate the time-course of effects of 5-HT uptake blockers on hypothalamic 5-HT1A receptors, their signal transduction mechanisms, and endocrine responses to 5-HT1A agonists. Specific Aim 2 will determine the dose-response effects of chronic exposure to 5-HT uptake blockers on 5-HT1A receptors, their signal transduction mechanisms, and hormone responses mediated by 5-HT1A receptors. So far, studies have used doses that are 10 fold higher than clinically relevant doses. This study will determine the minimal dose of fluoxetine that will reduce 5-HT1A receptor function. The final Specific Aim will determine the duration of altered 5- HT1A receptor function after withdrawal from 5-HT uptake blockers. A comparison of endocrine changes with biochemical indices of 5-HT1A receptor function may provide a model of withdrawal from 5-HT uptake blockers.

描述：（改编自申请人的摘要）该项目重点关注 慢性病后脑血清素（5-HT）神经元的药理学 接触 5-HT 摄取阻滞剂。 5-HT1A 受体功能受损 与神经和精神疾病有关。慢性的 暴露于 5-HT 摄取阻滞剂会降低 5-HT1A 受体功能 中脑中的血清素能细胞。然而，信息却很少 目前关于 5-HT 摄取阻滞剂的影响 下丘脑突触后 5-HT1A 受体。此外，还没有研究表明 研究了诸如时间进程、剂量反应等基本问题 5-HT 摄取阻滞剂对 5-HT 的影响的关系或持续时间 HT1A受体功能。申请人最近发现5-HT 摄取阻滞剂氟西汀（10 mg/kg/天，21 天）可降低 5-HT1A 受体介导的血浆ACTH和催产素反应呈时间依赖性 方式。单次注射氟西汀没有效果。假设 慢性暴露于 5-HT 摄取阻滞剂导致的进展 血清素能神经传递的适应性变化，导致 下丘脑 5-HT1A 受体功能降低。拟议的 研究将描述下丘脑突触后 5- 长期接触 5-HT 摄取阻滞剂会诱导 HT1A 受体。 生化方法将重点关注 5-HT1A 受体密度的变化 及其信号转导机制（与 G 蛋白偶联）。在 此外，下丘脑 5-HT1A 受体的反应性将 根据对特定 5-HT1A 的神经内分泌反应确定 激动剂。具体目标 1 将调查影响的时间进程 下丘脑 5-HT1A 受体上的 5-HT 摄取阻滞剂及其信号 转导机制和对 5-HT1A 激动剂的内分泌反应。 具体目标 2 将确定慢性药物的剂量反应效应 暴露于 5-HT1A 受体上的 5-HT 摄取阻滞剂，其信号 5-HT1A 介导的转导机制和激素反应 受体。到目前为止，研究使用的剂量比 临床相关剂量。这项研究将确定最小剂量 氟西汀会降低 5-HT1A 受体功能。决赛 具体目标将决定 5-HT1A 受体改变的持续时间 停用 5-HT 摄取阻滞剂后发挥作用。比较 内分泌变化与5-HT1A受体功能生化指标的关系 可能提供退出 5-HT 摄取阻滞剂的模型。