Serotonin Reuptake Inhibitors and 5-HT1A Receptors

5-羟色胺1A（5-HT 1A）受体通过不同的G蛋白介导不同的信号级联，所述G蛋白参与各种生理功能并且在情绪障碍的病因学和/或治疗中起作用。情绪障碍与HPA轴激活增加有关，HPA轴通过抗抑郁药恢复正常。在成年人下丘脑的神经内分泌神经元中，氟西汀（Prozac（R））和其他选择性重摄取抑制剂（SSRIs）使血浆激素（如ACTH和催产素）的5-HT 1A活化脱敏。 该提案的长期目标是通过了解急性与长期重复给药后各类激动剂在介导多个细胞内途径的5-HT受体信号传导中引起的机制来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-HT 1A受体信号传导的适应性变化相关，因此了解5-HT 1A受体介导神经内分泌神经元对急性和慢性暴露于不同类别5-HT激动剂的信号传导的机制至关重要。 基于我们的初步发现，5-HT 1A受体可以与不同群体的G蛋白偶联， MAP激酶和激素通过独立作用于急性受体激活的途径的反应 但表现出“串扰”，导致5-HT 1A介导的神经内分泌应答的脱敏， 重复给药，我们假设：MAP激酶激活在 催产素和CRF中5-HT 1A受体介导的激素信号的神经适应性变化 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将确定不同类别的激动剂对贩运的有效性 5-HT 1A受体与Gai/o蛋白结合并激活下丘脑MAP激酶和/或Gaz蛋白以刺激 激素反应;目标2;将确定介导5-HT 1A受体的特异性Ga蛋白亚型 激动剂激活下丘脑室旁核MAP激酶及5-HT 1A激活MAP的定位 目的3将确定催产素和CRF阳性神经元的细胞外信号调节激酶（pERK）的作用机制， 5-羟色胺/去甲肾上腺素再摄取抑制剂（SNRIs）使激素的5-HT 1A受体信号转导脱敏 催产素和CRF神经内分泌神经元的反应和MAP激酶的需要， 介导SNRI诱导的脱敏，目的4将确定重复施用 不同种类的多巴胺能激动剂对下丘脑5-HT 1A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-HT 1A受体信号通路的新机制以及临床使用的抗抑郁药物可能产生不同G蛋白介导的信号通路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性中的作用。这些信息对于确定可能导致SSRIs、SNRIs或其他开发用于治疗涉及5-HT 1A受体的各种精神病理学和情绪障碍的药物的临床疗效或“副作用”延迟的机制至关重要。

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.