Serotonin Reuptake Inhibitors and 5-HT1A Receptors

5-羟色胺再摄取抑制剂和 5-HT1A 受体

• 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
• 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

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）受体通过参与各种生理功能的不同G蛋白介导了各种信号级联，并在情绪障碍的病因和/或治疗中起作用。情绪障碍与通过抗抑郁药标准化的HPA轴的激活增加有关。在成年下丘脑中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（SSRIS）脱敏5-HT1A血浆激素（如ACTH和催产素）的激活。 该提案的长期目标是通过了解各种类型激动剂在急性和长期重复药物给药时介导多个细胞内途径的5-HT受体信号传导中所起的机制来制定更好的治疗策略。由于包括SSRI在内的各种药物的临床有效性与5-HT1A受体信号传导的自适应变化有关，因此了解5-HT1A受体介导神经内分泌神经元中的信号传导的机制至关重要，响应于5-HT激动剂的不同类别的急性暴露和慢性暴露。 根据我们的最初发现，5-HT1A受体可以将夫妇与不同的G蛋白息息 通过对急性受体激活独立起作用的途径，MAP激酶和激素反应都会产生 但展示“串扰”，导致5-HT1A介导的神经内分泌反应脱敏 重复药物给药，我们假设：MAP激酶激活在 5-HT1A受体介导的激素信号传导的神经适应性变化在催产素和CRF中 响应SSRI和SNRI药物，含有神经内分泌神经元。这将由 该项目的四个目标； AIM 1将确定不同类别的激动剂对贩运的有效性 5-HT1A受体到GAI/O蛋白，并激活下丘脑MAP激酶和/或GAZ蛋白刺激 激素反应； AIM 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 激酶（PERK）到催产素和CRF阳性神经元； AIM 3将确定该机制 5-羟色胺/去甲肾上腺素再摄取抑制剂（SNRI）脱敏5-HT1A受体信号传导 催产素和含有CRF的神经内分泌神经元的反应以及MAP激酶在 介导SNRI诱导的脱敏，AIM 4将决定重复给药的功效 不同类别的血清素能激动剂，使下丘脑5-HT1A受体介导的MAP激酶脱敏 信号。这些研究将提供有关下丘脑神经元中5-HT1A受体信号通路的新机制的重要新信息，以及临床使用的抗抑郁药可能在不同G蛋白介导的信号通路中产生适应性变化的机制。 这些研究将阐明MAP激酶在调节神经内分泌神经元对临床上使用的各种药物的反应性方面的作用。这些信息对于确定可能导致临床功效发作或SSRIS，SNRIS或其他用于治疗涉及5-HT1A受体的各种心理病理学和情绪障碍的药物的“副作用”的机制至关重要。