ANTIDEPRESSANTS AND SIGNAL TRANSDUCTION IN BRAIN

重度抑郁症是一种破坏性的疾病， 方面的影响.虽然抑郁症的药物治疗已经 这些药物已经使用了40多年，但并不总是有效， 需要长期给药。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），但治疗作用的机制， 慢性抗抑郁药仍然很大程度上未知。对慢性病的要求 治疗导致了这样的假设，即细胞和分子适应性， 升高的NE和5-HT水平介导了对 抗抑郁药识别关键的适应性可以提供 为开发更快的行动和更有效的信息 抗抑郁药我们实验室最近的研究提供了证据， cAMP信号转导级联的上调有助于这种作用 抗抑郁药治疗。慢性抗抑郁治疗增加了 cAMP反应元件结合蛋白（CREB）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）上调，表明BDNF是CREB的基因靶点， 抗抑郁治疗观察到这些效应是为了响应 给予NE和5-HT选择性再摄取抑制剂，提示 cAMP-CREB级联和BDNF的表达是 抗抑郁治疗。在这一相互竞争的更新中，建议进行研究， 扩展这些发现，并测试假设，激活的 cAMP-CBEB级联和BDNF诱导介导抗抑郁作用 治疗这将包括研究进一步表征 CREB和BDNF在体内和原代神经元培养物中的功能和表达。 此外，该提案的一个主要目标是直接测试 CREB和BDNF对抗抑郁反应模型，包括强迫游泳 测试和习得性无助范式。为了调节CREB和BDNF的水平， 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， 研究确定cAMP磷酸二酯酶（PDE 4）的亚型， 提出了cAMP的分解，包括PDE 4亚型的调节， 抗抑郁治疗和PDE 4无效突变小鼠的发育。

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.