Serotonin Reuptake Inhibitors and 5-HT1A Receptors

描述（由申请人提供）：选择性血清素再摄取抑制剂（SSRIs），如氟西汀（百忧解/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开始延迟2-3周。上一个资助期的研究表明，SSRIs对大鼠下丘脑突触后5-羟色胺lA （5-HT1A）受体产生强大的脱敏作用。这种脱敏是逐渐发生的（7-14天），对应于SSRIs治疗效果的2-3周延迟。因此，突触后5-HTIA受体的脱敏可能是SSRIs的一些治疗效果的模型。SSRI治疗开始后临床改善的长时间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大鼠SSRIs治疗期间突触后下丘脑5-HTIA受体系统同源脱敏的机制上，本建议的重点是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受体激活会导致大鼠下丘脑室旁核MAP激酶（ERK1/2）的快速磷酸化。我们的中心假设是Gz蛋白- map激酶信号通过SSRIs介导5-HTIA受体的脱敏。特异性目的1将检验Gz蛋白介导下丘脑5-HTIA受体介导的MAP激酶信号激活的假设。特异性目的2将验证Gz蛋白表达降低介导ssri诱导的下丘脑5-HTIA受体脱敏的假设。特异性Aim 3将验证MAP激酶信号传导介导ssri诱导的下丘脑突触后5-HTIA受体脱敏的假设。特异性Aim 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）。这些研究将深入了解突触后5-HTIA受体信号的体内调控，并将为情绪障碍的治疗提供新的靶点。

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.