Antidepressants: Signal Transduction and Gene Expression

描述（由申请人提供）：重度抑郁症是一种具有广泛社会经济影响的破坏性疾病。虽然抑郁症的药物治疗已经有40多年的历史，但这些药物并不总是有效的，它们需要数周甚至数月的治疗。大多数抗抑郁药的急性作用是通过抑制去甲肾上腺素（NE）和5-羟色胺（5-HT）的再摄取或分解而发生的，但慢性抗抑郁药治疗（ADT）的治疗作用机制仍不清楚。对长期ADT的需求导致了这样的假设，即细胞和分子对NE和5-HT水平升高的适应介导了治疗反应。我们实验室的研究表明，cAMP反应元件结合蛋白（cAMP-CREB）信号转导级联和该途径的靶点BDNF（脑源性神经营养因子）有助于ADT的作用。我们已经证明，不同类别的抗抑郁药，包括NE和5-HT选择性再摄取抑制剂，增加CREB和BDNF在边缘结构中的表达，CREB和BDNF足以在行为模型中产生ADT反应。这项工作导致了抑郁症的神经营养假说，这是该领域的一个领先理论，这项提议的目的之一是通过确定CREB和BDNF是否是必要的来验证这一假说，以及是否足以进行ADT反应。这些研究还表明，cAMP-CREB或BDNF信号传导的激活将产生ADT应答。这得到了研究的支持，研究表明，通过抑制cAMP磷酸二酯酶4型（PDE 4）激活cAMP-CREB级联的药物在啮齿动物模型和人体中产生ADT反应。本提案的另一个主要目的是确定ADT应答的PDE 4亚型。一个相关的目的是确定BDNF信号通路的激活是否也产生ADT反应，并研究该通路中的蛋白质，特别是蛋白磷酸酶，可以作为药物开发的靶点。因为没有针对这些靶点的选择性药物，我们将使用互补方法，包括我们已经工程化或获得的无效突变小鼠和用于野生型或显性阴性基因局部表达的病毒载体。这些研究将进一步表征ADT作用的机制，并确定新的药物靶点，以开发更快起效和更有效的药物。

DESCRIPTION (provided by applicant): 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 weeks or even months of treatment. 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 antidepressant treatment (ADT) remain largely unknown. The requirement for long-term ADT has lead to the hypothesis that cellular and molecular adaptations to elevated levels of NE and 5-HT mediate the therapeutic response. Studies from our laboratory have demonstrated that the cAMP-CREB (cAMP response element binding protein) signal transduction cascade and a target of this pathway, BDNF (brain derived neurotrophic factor), contribute to the action of ADT. We have demonstrated that different classes of antidepressants, including NE and 5-HT selective reuptake inhibitors, increase CREB and BDNF expression in limbic structures, and that CREB and BDNF are sufficient to produce an ADT-response in behavioral models. This work has resulted in the neurotrophic hypothesis of depression, a leading theory in the field, and one of the aims of this proposal is to test this hypothesis by determining if CREB and BDNF are necessary, as well as sufficient for an ADT-response. These studies also indicate that activation of cAMP-CREB or BDNF signaling would produce an ADT response. This is supported by studies demonstrating that drugs that activate the cAMP-CREB cascade, by inhibition of the cAMP phosphodiesterase type 4 (PDE4), produces an ADT-response in rodent models and in humans. Another major aim of this proposal is to identify which of the PDE4 subtype(s) underlies the ADT response. A related aim is to determine if activation of the BDNF signaling pathway also produces an ADT response, and to investigate proteins in this pathway, particularly protein phosphatases, that could be targeted for drug development. Because there are no selective drugs for these targets, we will use complimentary approaches, including null mutant mice that we have engineered or obtained and viral vectors for local expression of wild type or dominant negative genes. These studies will further characterize the mechanisms underlying the action of ADT and identify novel drug targets for the development of faster acting and more efficacious medications.