Post-Synaptic Mechanisms for Depression and Antidepressants: Studies in Model Sy

描述(申请人提供)：尽管经过几十年的研究，抗抑郁药物(或抑郁障碍)的分子/细胞作用基础还没有出现统一的假设。在过去的几年里，我们已经提出，除了突触前靶点(摄取部位)，一些抗抑郁药物还有突触后的作用机制。为此，我们观察到，用一些化学上不同的抗抑郁化合物慢性处理C6胶质瘤细胞，可以将异三聚体G蛋白GSA从脂筏中移出，进入与腺苷环化酶更紧密的结合。我们还看到，在这个模型系统中，GSA和微管蛋白(细胞骨架的一种成分)之间的相互作用因抗抑郁治疗而减弱。这项研究将研究抗抑郁剂诱导的GSA从脂筏中移出，以及这对G蛋白信号系统以及最终对突触结构发展的影响。许多实验将使用荧光G蛋白类似物以及荧光细胞骨架蛋白和脂筏标记实时进行(在一段时间内)。这些研究将在神经细胞和神经胶质细胞系以及原代大鼠海马神经元中进行。这些研究还将致力于通过开发旨在干扰GSA和微管蛋白之间相互作用的方面的探针，并在我们的模型系统中确定此类探针是否具有抗抑郁特性，来建立这一过程与抗抑郁作用的相关性。这种分子相互作用以及GSA和脂筏之间相互作用的改变可能被证明是抑郁症和抗抑郁药物治疗成功的生物标志物。希望这项研究的成功完成不仅将揭示抑郁症的病因和治疗的可能分子机制，而且将为新的基于蛋白质组的治疗策略指明方向。 从社会和经济的角度来看，抑郁症的负担仅次于缺血性心脏病。我们已经开发了一个模型系统，使用培养的细胞来确定抗抑郁治疗的有效性，并确定一种机制，即可以使用如此多的不同药物来治疗相同的疾病。这些研究应该有助于确定抑郁症和抗抑郁药物作用的分子途径。了解这些应该揭示抑郁症的生物标记物和治疗这种疾病的新类别化合物。

DESCRIPTION (provided by applicant): Despite several decades of research, no unifying hypothesis for a molecular/cellular basis of action for antidepressant drugs (or depressive disorders) has emerged. Over the last several years, we have suggested that, in addition to pre-synaptic targets (uptake sites), a number of antidepressant drugs have a post-synaptic mechanism of action. Toward this end, we have observed that chronic treatment of C6 glioma cells with a number of chemically diverse antidepressant compounds moves the heterotrimeric G protein Gsa out of lipid rafts and into a closer association with adenylyl cyclase. We have also seen that the interaction between Gsa and tubulin, an element of the cytoskeleton, is diminished by antidepressant treatment in this model system. This study will examine the antidepressant-induced movement of Gsa out of lipid rafts and the consequences of this for G protein signaling systems and, ultimately, for development of synaptic structures. Many of the experiments will be done in real-time (over a period of days) using florescent G protein analogs as well as fluorescent cytoskeletal proteins and lipid raft markers. These studies will be carried out in neural and glial cell lines as well as in primary rat hippocampal neurons. These studies will also endeavor to establish the relevance of this process for antidepressant action, by developing probes designed to disrupt aspects of the interaction between Gsa and tubulin and determining whether such probes have antidepressant properties in our model system. This molecular interaction as well as altered interaction between Gsa and lipid rafts may prove to be a biological marker for both depression and for successful antidepressant treatment. It is hoped that successful completion of this study will not only reveal possible molecular mechanisms for the etiology and treatment of depression, but will point the way to new, proteomic-based strategies for treatment. The burden of depression, both from a societal and economic standpoint, ranks second only to ischemic heart disease. We have developed a model system, using cultured cells, to determine the effectiveness of antidepressant treatment and to ascertain a mechanism whereby so many different drugs can be used to treat the same disorder. These studies should help to identify molecular pathways for both depression and the actions of antidepressant drugs. Understanding these should reveal both biological markers for depression and new classes of compounds to treat this disorder.