Structural/Trophic Hypothesis for Antidepressant Actions

描述（由申请人提供）：抗抑郁药物作用的机制尚不清楚。在本申请中，我们提出抗抑郁药物通过经典的营养机制起作用，即皮质和边缘系统中中央单胺轴突的末端分支的增殖（发芽）。我们还提出，介导这些结构效应的分子信号是神经营养因子，例如，对于5-羟色胺系统，关键信号是脑源性神经营养因子（BDNF）。我们的实验设计采用细胞和分子方法学的逐步方法，包括转基因小鼠。我们首先评估5-羟色胺（5-HT）和去甲肾上腺素（NE）促进化合物在新皮层，海马和皮层下边缘系统的选定区域引起5-HT和NE发芽的能力。同时，我们评估抗抑郁药在增强相同区域神经营养因子表达和转导中的作用，重点是BDNF和5-HT再摄取抑制剂/增强剂。我们随后测试废除BDNF表达/结合的策略（例如用抗体和清除肽阻断BDNF或用转基因方法部分消除BDNF）是否抑制抗抑郁药对5-HT纤维发芽的影响。最后，我们评估的意义，营养机制的介导的抗抑郁作用的BDNF +/-小鼠在实验室抑郁症模型。与此同时，我们的提案寻求抗抑郁药物作用的新假设，这对于将情绪障碍理解为中枢单胺系统结构可塑性钝化的疾病具有意义。

DESCRIPTION (provided by applicant): Mechanisms of antidepressant drug actions are not clearly understood. In the present application, we propose that antidepressant drugs work via a classical trophic mechanism, i.e. proliferation of terminal branches (sprouting) of central monoamine axons in cortex and the limbic system. We also propose that the molecular signals mediating these structural effects are neurotrophins, e.g. for the serotonin system, the critical signal is brain-derived neurotrophic factor (BDNF). Our experimental design takes a stepwise approach using cellular and molecular methodologies, including transgenic mice. We first evaluate the ability of serotonin (5-HT)- and norepinephrine (NE)-promoting compounds to cause 5-HT and NE sprouting in selected areas of neocortex, hippocampus and the subcortical limbic system. In parallel, we evaluate the role of antidepressants in enhancing neurotrophin expression and transduction in the same areas, focusing on BDNF and 5-HT reuptake inhibitors/enhancersx We subsequently test whether strategies that abolish BDNF expression/binding (such as blocking BDNF with antibodies and scavenging peptides or partially eliminating BDNF with transgenic approaches) inhibit the effects of antidepressants on 5-HT fiber sprouting. Finally, we assess the significance of trophic mechanisms for the mediation of antidepressant effects using BDNF +/- mice in laboratory models of depression. In concert, our proposal pursues a novel hypothesis for the effects of antidepressant drugs which has implications for an understanding of mood disorders as disorders of blunted structural plasticity of central monoamine systems.