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: 7009552
• 负责人: GEORGE BATTAGLIA
• 金额: $ 33.42万
• 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 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009552
• 关键词: enzyme activity; fluoxetine; guanine nucleotide binding protein; hypothalamus; laboratory rat; mitogen activated protein kinase; pharmacokinetics; protein binding; receptor expression; receptor sensitivity; serotonin inhibitor; serotonin receptor; transcription factor

DESCRIPTION (provided by applicant): Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac/R) have revolutionized psychiatry. However, a major problem with SSRIs is a 2-3 week delay in therapeutic onset. Studies from the last funding period indicate that SSRIs produce a robust desensitization of hypothalamic post-synaptic serotonin lA (5-HT1A) receptors in rats. This desensitization has a gradual onset (7-14 days), corresponding with the 2-3 week delay in therapeutic effects of SSRIs. Hence, desensitization of post-synaptic 5-HTIA receptors could be a model of some of the therapeutic effects of SSRIs. The long delay in clinical improvement after the onset of SSRI treatment remains a fundamental problem that may be overcome by a more comprehensive understanding of the underlying basis for 5-HT1A receptor desensitization. Therefore this competitive renewal will focus on the mechanisms responsible for the homologous desensitization of post-synaptic hypothalamic 5-HTIA receptor systems during treatment of rats with SSRIs, The focus of this proposal is on the 5-HT1A receptor - Gz protein - mitogen-activated protein kinase (MAPK also known as ERK1/2) cascade. The MAP kinase cascade (Raf-MEK-ERK) is involved in many cellular processes including receptor desensitization. Our preliminary studies indicate that 5-HT1A-receptor activation produces a rapid phosphorylation of MAP kinase (ERK1/2) in the rat hypothalamic paraventricular nucleus. Our central hypothesis is that Gz protein-MAP kinase signaling mediates the desensitization of 5-HTIA receptors by SSRIs. Four specific aims are proposed: Specific Aim 1 will test the hypothesis that Gz proteins mediate the 5-HTIA receptor-mediated activation of MAP kinase signaling in the hypothalamus. Specific Aim 2 will test the hypothesis that reduced expression of Gz proteins mediates SSRI-induced desensitization of hypothalamic 5-HTIA receptors. Specific Aim 3 will test the hypothesis that MAP kinase signaling mediates the SSRI-induced desensitization of post-synaptic 5-HTIA receptors in the hypothalamus. Specific Aim 4 will identify the transcription factors (c-myc and Spl) that mediate fluoxetine-induced desensitization of 5-HTIA receptors. The proposed studies will provide an in-depth understanding of the regulation of post-synaptic 5-HTIA receptor signaling in vivo and will identify new targets for the treatment of mood disorders.

描述（由申请人提供）：选择性血清素再摄取抑制剂（SSRI）如氟西汀（Prozac/R）已经彻底改变了精神病学。然而，SSRIs 的一个主要问题是治疗起效延迟 2-3 周。上一个资助期的研究表明，SSRIs 对大鼠下丘脑突触后血清素 IA (5-HT1A) 受体产生强烈的脱敏作用。这种脱敏作用是逐渐发生的（7-14 天），与 SSRI 的治疗效果延迟 2-3 周相对应。因此，突触后 5-HTIA 受体的脱敏可能是 SSRI 某些治疗作用的模型。 SSRI 治疗开始后临床改善的长期延迟仍然是一个基本问题，可以通过更全面地了解 5-HT1A 受体脱敏的根本基础来克服。因此，这一竞争性更新将重点关注在用 SSRIs 治疗大鼠期间负责突触后下丘脑 5-HTIA 受体系统同源脱敏的机制，本提案的重点是 5-HT1A 受体 - Gz 蛋白 - 有丝分裂原激活蛋白激酶（MAPK 也称为 ERK1/2）级联。 MAP 激酶级联 (Raf-MEK-ERK) 参与许多细胞过程，包括受体脱敏。我们的初步研究表明，5-HT1A 受体激活会导致大鼠下丘脑室旁核中 MAP 激酶 (ERK1/2) 快速磷酸化。我们的中心假设是 Gz 蛋白-MAP 激酶信号传导介导 SSRIs 对 5-HTIA 受体的脱敏作用。提出了四个具体目标： 具体目标 1 将检验 Gz 蛋白介导下丘脑中 5-HTIA 受体介导的 MAP 激酶信号传导激活的假设。具体目标 2 将检验 Gz 蛋白表达减少介导 SSRI 诱导的下丘脑 5-HTIA 受体脱敏的假设。具体目标 3 将检验以下假设：MAP 激酶信号传导介导 SSRI 诱导的下丘脑突触后 5-HTIA 受体脱敏。具体目标 4 将鉴定介导氟西汀诱导的 5-HTIA 受体脱敏的转录因子（c-myc 和 Spl）。拟议的研究将深入了解体内突触后 5-HTIA 受体信号传导的调节，并将确定治疗情绪障碍的新靶点。