Serotonin Reuptake Inhibitors and 5-HT1A Receptors

5-羟色胺再摄取抑制剂和 5-HT1A 受体

基本信息

批准号：
7812506
负责人：
GEORGE BATTAGLIA
金额：
$ 38.02万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-30 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7812506
关键词：
ADP ribosylation Acute Adenoviruses Adrenergic Agents Adult Adverse drug effect Adverse effects Aftercare Agonist Antidepressive Agents Anxiety Asses Cells Chronic Clinical Clinical effectiveness Corticotropin Corticotropin-Releasing Hormone Dependence Disease Dose Drug Delivery Systems Drug Exposure Drug usage Effectiveness Etiology Exhibits Exposure to Extracellular Signal Regulated Kinases Fenfluramine Fluoxetine Funding GTP-Binding Proteins Goals Hormones Hypothalamic structure Injection of therapeutic agent Longevity MAP Kinase Modules MEK inhibition MEKs Maps Measures Mediating Mitogen-Activated Protein Kinases Mood Disorders Neurons Neurosecretory Systems Norepinephrine Oxytocin Paroxetine Pathway interactions Pertussis Toxin Pharmaceutical Preparations Pharmacological Treatment Phosphorylation Phosphotransferases Physiological Plasma Play Population Progress Reports Protein Family Proteins Prozac Psychopathology Rattus Receptor Activation Receptor Signaling Regulation Research Role Selective Serotonin Reuptake Inhibitor Serotonin Serotonin Agonists Serotonin Receptor 5-HT1A Signal Pathway Signal Transduction Small Interfering RNA Specificity Synapses Testing Therapeutic Time adrenergic base cell type clinical efficacy clinically relevant depression desensitization duloxetine extracellular hormone sensitivity in vivo inhibitor/antagonist novel paraventricular nucleus postsynaptic prevent receptor receptor function receptor-mediated signaling research study resilience response reuptake serotonin receptor treatment strategy uptake

项目摘要

Serotonin1A (5-HT1A) receptors mediate diverse signaling cascades via different G-proteins that are involved in various physiological functions and play a role in the etiology and/or treatment of mood disorders. Mood disorders are associated with increased activation of the HPA axis that is normalized by antidepressants. In neuroendocrine neurons in the adult hypothalamus, fluoxetine (Prozac(R)) and other serotonin-selective reuptake inhibitors (SSRIs) desensitize 5-HT1A activation of plasma hormones such as ACTH and oxytocin. The long-term objective of this proposal is to develop better treatment strategies by understanding the mechanisms invoked by various classes of agonists in mediating 5-HT receptor signaling of multiple intracellular pathways upon acute versus long-term repetitive drug administration. Because the clinical effectiveness of various drugs including the SSRIs is associated with adaptive changes in 5-HT1A receptor signaling, it is critical to understand the mechanisms by which 5-HT1A receptors mediate signaling in neuroendocrine neurons in response to the acute and chronic exposure to different classes of 5-HT agonists. Based on our initial findings that 5-HT1A receptors can couple to different populations of G proteins to activate both MAP kinase and hormone responses via pathways that act independently upon acute receptor activation but exhibit "cross-talk" resulting in desensitization of 5-HT1A mediated neuroendocrine response upon repetitive drug administration, we HYPOTHESIZE: MAP kinase activation plays an integral role in the neuroadaptive changes in 5-HT1A receptor-mediated hormone signaling in oxytocin and CRF containing neuroendocrine neurons in response to SSRIs and SNRI drugs. This will be tested by the four aims of this project; Aim 1 will determine effectiveness of different classes of agonists to traffick 5-HT1A receptors to Gai/o proteins and activate hypothalamic MAP kinase and/or Gaz-proteins to stimulate hormone responses; Aim 2;will determine the specific Ga-protein subtypes that mediate 5-HT1A receptor agonist activation of MAP kinase in the hypothalamic PVN and the localization of 5-HT1A activated MAP kinase (pERK) to oxytocin- and CRF-positive neurons; Aim 3 will determine the mechanisms by which serotonin/norepinephrine reuptake inhibitors (SNRIs) desensitize 5-HT1A receptor signaling of hormone responses in oxytocin and CRF-containing neuroendocrine neurons and the requirement of MAP kinase in mediating SNRI-induced desensitization, and Aim 4 will determine the efficacy of repetitive administration of different classes of serotonergic agonists to desensitize hypothalamic 5-HT1A receptor mediated MAP kinase signaling. These studies will provide important new information regarding the novel mechanisms of 5-HT1A receptor signaling pathways in hypothalamic neurons and the mechanisms by which clinically used antidepressant drugs may produce adaptive changes in signaling pathways mediated by different G proteins. These studies will elucidate role of MAP kinase in regulating the responsiveness of neuroendocrine neurons to various classes of drugs used clinically. This information is critical to identifying the mechanisms that may contribute to delays in the onset of clinical efficacy or the "side effects" of SSRIs, SNRIs or other drugs developed to treat various psychopathologies and mood disorders involving 5-HT1A receptors.

血清素 1A (5-HT1A) 受体通过不同的 G 蛋白介导多种信号级联，这些信号级联涉及多种生理功能，并在情绪障碍的病因和/或治疗中发挥作用。情绪障碍与 HPA 轴激活增加有关，而 HPA 轴可通过抗抑郁药物恢复正常。在成人下丘脑的神经内分泌神经元中，氟西汀 (Prozac(R)) 和其他 5-羟色胺选择性再摄取抑制剂 (SSRI) 可使血浆激素（如 ACTH 和催产素）的 5-HT1A 激活变得不敏感。该提案的长期目标是通过了解各类激动剂在急性与长期重复给药时介导多种细胞内途径的 5-HT 受体信号传导的机制，开发更好的治疗策略。由于包括 SSRIs 在内的各种药物的临床有效性与 5-HT1A 受体信号传导的适应性变化相关，因此了解 5-HT1A 受体介导神经内分泌神经元中的信号传导以响应急性和慢性暴露于不同环境的机制至关重要。 5-HT 激动剂的类别。根据我们的初步发现，5-HT1A 受体可以与不同的 G 蛋白群体偶联以激活 MAP 激酶和激素反应均通过独立于急性受体激活的途径进行反应但表现出“串扰”，导致 5-HT1A 介导的神经内分泌反应脱敏重复给药，我们假设：MAP 激酶激活在催产素和 CRF 中 5-HT1A 受体介导的激素信号传导的神经适应性变化含有对 SSRI 和 SNRI 药物有反应的神经内分泌神经元。这将由该项目的四个目标；目标 1 将确定不同类别激动剂贩运的有效性 Gai/o 蛋白的 5-HT1A 受体并激活下丘脑 MAP 激酶和/或 Gaz 蛋白以刺激激素反应；目标 2；将确定介导 5-HT1A 受体的特定 Ga 蛋白亚型下丘脑 PVN 中 MAP 激酶的激动剂激活和 5-HT1A 激活 MAP 的定位催产素和 CRF 阳性神经元的激酶 (pERK)；目标 3 将确定机制血清素/去甲肾上腺素再摄取抑制剂 (SNRI) 使 5-HT1A 受体信号传导脱敏催产素和含有 CRF 的神经内分泌神经元的反应以及 MAP 激酶的需求介导 SNRI 诱导的脱敏，目标 4 将确定重复给药的功效不同类别的血清素激动剂使下丘脑 5-HT1A 受体介导的 MAP 激酶脱敏发信号。这些研究将为下丘脑神经元5-HT1A受体信号通路的新机制以及临床使用的抗抑郁药物可能对不同G蛋白介导的信号通路产生适应性变化的机制提供重要的新信息。这些研究将阐明 MAP 激酶在调节神经内分泌神经元对临床使用的各类药物的反应中的作用。这些信息对于确定可能导致临床疗效延迟或 SSRI、SNRI 或其他用于治疗涉及 5-HT1A 受体的各种精神病理学和情绪障碍的药物的“副作用”的机制至关重要。