Structural/Trophic Hypothesis for Antidepressant Actions

描述（由申请人提供）：抗抑郁药物的作用机制尚不清楚。在目前的应用中，我们提出抗抑郁药物通过经典的营养机制起作用，即皮层和边缘系统中央单胺轴突末端分支的增殖（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，例如对血清素系统来说，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逐步进行，包括转基因小鼠。我们首先评估了5-羟色胺（5-HT）和去甲肾上腺素（NE）促进化合物在新皮层、海马和皮质下边缘系统的选定区域引起5-HT和NE发芽的能力。同时，我们评估了抗抑郁药在增强神经营养因子表达和转导方面的作用，重点关注BDNF和5-HT再摄取抑制剂/增强剂。我们随后测试了消除BDNF表达/结合的策略（如用抗体和清除肽阻断BDNF或用转基因方法部分消除BDNF）是否抑制了抗抑郁药对5-HT纤维发芽的影响。最后，我们在实验室抑郁症模型中使用BDNF +/-小鼠来评估营养机制在抗抑郁作用中的作用。与此同时，我们的研究提出了一种新的抗抑郁药物作用假设，这有助于理解情绪障碍是中枢单胺系统结构可塑性减弱的障碍。

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.