Serotonin Reuptake Inhibitors and 5-HT1A Receptors

描述(由申请人提供)：选择性5-羟色胺再摄取抑制剂(SSRI)，如氟西汀(Prozac/R)，使精神病学发生了革命性的变化。然而，SSRIs的一个主要问题是治疗开始延迟2-3周。上一次资助期的研究表明，SSRIs对大鼠下丘脑突触后5-羟色胺1a(5-HT1a)受体有很强的脱敏作用。这种脱敏是一个逐步发生的过程(7-14天)，与SSRIs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SSRIs治疗效果的一个模型。在SSRI治疗开始后，临床改善的长期延迟仍然是一个根本问题，可以通过更全面地了解5-HT1A受体脱敏的潜在基础来克服。因此，这一竞争性更新将集中在SSRIs治疗大鼠过程中导致突触后下丘脑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-丝裂原活化蛋白激酶(MAPK，也称为ERK1/2)级联。MAP激酶级联(Raf-MEK-ERK)参与了包括受体脱敏在内的许多细胞过程。我们的初步研究表明，5-HT1A受体的激活在大鼠下丘脑室旁核产生MAP激酶(ERK1/2)的快速磷酸化。我们的中心假设是Gz蛋白-MAP激酶信号介导了SSRIs对5-HTIA受体的脱敏作用。提出了四个特定的目标：特定目标1将验证Gz蛋白介导5-HTIA受体介导的下丘脑MAP激酶信号激活的假设。特定目的2将验证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将验证MAP激酶信号介导SSRI诱导的突触后下丘脑5-HTIA受体脱敏的假说。特异性目标4将确定介导氟西汀诱导的5-HTIA受体脱敏的转录因子(c-myc和SPL)。这项拟议的研究将提供对体内突触后5-HTIA受体信号调节的深入了解，并将为情绪障碍的治疗确定新的靶点。

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.