Serotonin Reuptake Inhibitors and 5-HT1A Receptors

5-HT1A受体通过不同的G蛋白介导不同的信号级联反应，这些G蛋白参与不同的生理功能，在情绪障碍的病因和/或治疗中发挥作用。情绪障碍与HPA轴的激活增加有关，HPA轴被抗抑郁药物正常化。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)5-HT1A的激活变得不敏感。 这一建议的长期目标是通过了解不同类别的激动剂在急性与长期重复给药时介导多个细胞内途径的5-羟色胺受体信号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疗效与5-HT1a受体信号的适应性变化有关，因此了解5-HT1a受体介导神经内分泌神经元信号转导的机制对不同类别的5-HT1a激动剂的急性和慢性暴露至关重要。 基于我们的初步发现，5-HT1A受体可以与不同群体的G蛋白偶联来激活 MAP激酶和激素反应都是通过独立作用于急性受体激活的途径实现的 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 5-HT1A受体介导的激素信号在催产素和慢性肾功能衰竭中的神经适应性变化 含有对SSRIs和SNRI药物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将确定不同类别的促进剂对贩运的有效性 5-HT1a受体结合Ga1/o蛋白激活下丘脑MAPK和/或Gaz-蛋白刺激 激素反应；目标2；将确定介导5-HT1A受体的特定GA蛋白亚型 下丘脑室旁核MAP的激动剂激活及5-HT1A型MAP的定位 激酶(PERK)对催产素和CRF阳性神经元的作用；目标3将确定 5-羟色胺/去甲肾上腺素再摄取抑制剂(SNRIs)脱敏激素5-HT1a受体信号 大鼠神经内分泌神经元对催产素和促肾上腺皮质激素释放因子的反应及对MAP-K的需求 介导SNRI诱导的脱敏，目标4将确定重复给药的疗效 不同类型5-羟色胺能激动剂对下丘脑5-HT1a受体介导的MAP激酶的脱敏作用 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在不同G蛋白介导的信号通路中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种药物的反应性中的作用。这些信息对于确定可能导致临床疗效延迟或SSRIs、SNRIs或其他药物的“副作用”的机制至关重要，这些药物是为治疗涉及5-HT1a受体的各种精神病理和情绪障碍而开发的。

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.