Antidepressants and Fibroblast Growth Factor

说明(申请人提供)：抗抑郁药物疗效的作用机制(S)尚不完全清楚。目前关于抑郁症病理的一种观点认为，这种精神疾病是由突触连接功能障碍引起的，可能是由于突触接触的丧失。相反，最近的实验数据表明，抗抑郁药物的治疗作用可能涉及它们增加神经发生和突触强度的能力。这些特性可能更多地来自神经营养因子合成的诱导，而不是单胺受体的激活。初步数据表明，抗抑郁剂增加了碱性成纤维细胞生长因子(FGF2)的合成，这是一种神经营养因子，对儿茶酚胺能神经元发挥神经营养活性，并促进成年大脑中的神经发生。这些实验数据提出了一个新的、具有挑战性的、但及时的假设，即抑郁症的特征是缺乏营养支持，抗抑郁药物通过诱导FGF2的合成来恢复成年大脑的突触可塑性。作为检验这些假说的实验工具，我们建议使用一种名为慢性不可预测的轻度应激(CMS)的抑郁症大鼠模型，在该模型中，大鼠出现快感缺失，这是严重抑郁症的核心症状之一。特别是，我们计划研究CMS是否下调大脑中FGF2的表达(mRNA和蛋白质)，以及地塞帕明和氟西汀等抗抑郁药物是否会逆转这种下调。此外，由于CMS可引起额叶皮质的细胞凋亡，我们建议通过检测抗抑郁药和FGF2限制凋亡细胞死亡的能力来测试抗抑郁药在这种抑郁动物模型中的神经保护活性。通过检测CMS大鼠几个脑区caspase-3活性和原位末端脱氧核苷酸转移酶介导的DTP缺口末端标记(TUNEL)染色来检测细胞的凋亡。总体而言，本研究的结果将为抗抑郁药物影响成熟大鼠神经元可塑性的机制提供一个重大突破。这项研究的数据可能有助于阐明抗抑郁药对情感性精神障碍的治疗效果。

DESCRIPTION (provided by applicant): The mechanism(s) responsible for the therapeutic effect of antidepressant drugs is not completely understood. One current view regarding the pathology of depression proposes that this mental illness results from dysfunction of synaptic connections, perhaps due to the loss of synaptic contacts. Conversely, recent experimental data have suggested that the therapeutic action of antidepressants may involve their ability to increase neurogenesis and synaptic strength. These properties may result more from the induction of neurotrophic factor synthesis than activation of monoamine receptors. This suggestion is supported by preliminary data showing that antidepressants increase the synthesis of basic fibroblast growth factor (FGF2), a neurotrophic factor that exerts neurotrophic activity on catecholaminergic neurons and promotes neurogenesis in the adult brain. These experimental data give rise to a novel and challenging but timely hypotheses that depression is characterized by lack of trophic support and that antidepressants restore synaptic plasticity in adult brain by inducing the synthesis of FGF2. As an experimental tool to test these hypotheses, we propose to use a rat model of depression termed chronic, unpredictable mild stress (CMS), by which rats develop anhedonia, one of the core symptoms of major depression. In particular, we plan to investigate whether CMS down-regulates FGF2 expression (mRNA and protein) in the brain and whether antidepressants such as desipramine and fluoxetine will reverse this down-regulation. Moreover, since CMS evokes apoptotic cell death in the frontal cortex, we propose to test the neuroprotective activity of antidepressants in this animal model of depression by examining the ability of antidepressants and FGF2 to limit apoptotic cell death. Apoptosis will be determined by measuring caspase- 3 activation and in situ terminal deoxynucleotidyl transferase-mediated biotinylated DTP nick end labeling (TUNEL) staining in several brain areas of CMS rats. Overall, the results of the present study will provide a major break-through on the mechanisms whereby antidepressants affect neuronal plasticity in mature rats. Data from this proposal may help elucidate the therapeutic efficacy of antidepressants in affective disorders.