ANTIDEPRESSANTS AND SIGNAL TRANSDUCTION IN BRAIN

抑郁症是一种破坏性的疾病，具有广泛的社会经济意义。 效果。尽管抑郁症的药物治疗一直是 这些药物已经有40多年的历史了，但并不总是有效的，它们 需要长期服用。大多数抗抑郁药的急性作用发生在 通过抑制去甲肾上腺素(NE)的再摄取或分解 5-羟色胺(5-HT)，但其治疗作用的机制 慢性抗抑郁药物在很大程度上仍不为人所知。对慢性病的要求 治疗导致了一种假设，即细胞和分子适应 去甲肾上腺素和5-羟色胺水平升高介导治疗反应 抗抑郁药。关键适应的识别可以提供 发展信息更快、更有效的行动 抗抑郁药。我们实验室最近的研究提供了证据表明 CAMP信号转导通路的上调参与了这一作用 抗抑郁药物的治疗。慢性抗抑郁药物治疗增加了 CAMP反应元件结合蛋白在边缘脑中的表达 地区。此外，脑源性神经营养因子的表达 (BDNF)表达上调，提示BDNF是CREB的基因靶点。 抗抑郁治疗。观察到这些影响是为了响应 同时给予去甲肾上腺素和5-羟色胺选择性再摄取抑制剂，提示 CAMP-CREB级联反应和BDNF的表达是骨肉瘤的共同靶点 抗抑郁治疗。在这场相互竞争的更新中，建议进行以下研究 扩展这些发现，并测试假设，激活 CAMP-CBEB级联反应和脑源性神经营养因子的诱导介导抗抑郁作用 治疗。这将包括进一步确定监管的特征的研究 CREB和BDNF在体内和原代培养神经元中的功能和表达。 此外，这项建议的一个主要目标是直接测试 CREB和BDNF在包括强迫游泳在内的抗抑郁药反应模型中的作用 测试和习得的无助感范式。调节脑内CREB和BDNF的水平 对于成年动物的大脑，将使用两种互补的方法：病毒 在大鼠和可诱导的区域特异性转基因小鼠中表达。最后， CAMP磷酸二酯酶(PDE4)催化亚型的鉴定研究 CAMP的分解被提出，包括调节PDE4亚型。 PDE4基因缺失突变小鼠的抗抑郁治疗及发育。

Major depressive illness is a devastating disorder with broad socioeconomic effects. Although pharmacological treatments for depression have been available for over 40 years, these drugs are not always effective and they require chronic administration. The acute actions of most antidepressants occur via inhibition of the reuptake or breakdown of norepinephrine (NE) and serotonin (5-HT), but the mechanisms underlying the therapeutic actions of chronic antidepressants remain largely unknown. The requirement for chronic treatment has lead to the hypothesis that cellular and molecular adaptations to elevated levels of NE and 5-HT mediate the therapeutic response to antidepressants. Identification of the critical adaptations could provide information for the development of faster acting and more efficacious antidepressants. Recent studies from our laboratory have provided evidence that up-regulation of the cAMP signal transduction cascade contributes to the action of antidepressant treatment. Chronic antidepressant treatment increases the expression of the cAMP-response element binding protein (CREB) in limbic brain regions. In addition, the expression of brain derived neurotrophic factor (BDNF) is up regulated, suggesting that BDNF is a gene target of CREB and antidepressant treatment. These effects are observed in response to administration of both NE and 5-HT selective reuptake inhibitors, suggesting that the cAMP-CREB cascade and expression of BDNF are common targets of antidepressant treatment. In this competing renewal, studies are proposed to extend these findings and to test the hypothesis that activation of the cAMP-CBEB cascade and induction of BDNF mediate the action of antidepressant treatment. This will include studies to further characterize the regulation of CREB and BDNF function and expression in vivo and in primary neuronal cultures. Moreover, a major goal of this proposal is to directly test the influence of CREB and BDNF on antidepressant-responsive models, including the forced swim test and learned helplessness paradigms. To modulate levels of CREB and BDNF in the brains of adult animals, two complementary approaches will be used: viral expression in rats and inducible, region specific transgenic mice. Finally, studies to identify the isoforms of cAMP phophodiesterase (PDE4) that catalyzes the breakdown of cAMP are proposed, including regulation of PDE4 isoforms by antidepressant treatment and development of PDE4 null mutant mice.