Cellular Mechanisms of Antidepressant Action

描述（由申请人提供）：目前的提案旨在了解目前用于治疗各种抑郁和焦虑相关疾病的药物的作用模式。虽然选择性5 -羟色胺再摄取抑制剂（SSRI）是最常用的抗抑郁药和抗焦虑药，但其作用机制，特别是其延迟（4-6周）起效的原因，在很大程度上是未知的。我们提出要测试的一般假设是，慢性抗抑郁药引起的海马神经发生增加有助于这些药物的行为影响。我们和其他人已经证明，各种慢性抗抑郁治疗导致海马齿状回的神经发生增加。我们还表明，长期抗抑郁药物治疗可以减少某些与焦虑相关的行为反应。最后，我们开发了两种不同的操作方法（遗传方法和放射方法），可以破坏抗抑郁药诱导的海马神经发生，并抑制抗抑郁药诱导的行为反应。基因操作是编码5-HT1A受体的基因的缺失；由此产生的基因敲除小鼠对SSRIs如氟西汀对神经发生和行为的影响不敏感。放射操作包括对小鼠大脑中含有海马的区域进行x射线照射；这样的治疗可以防止氟西汀对神经发生和行为的影响。这两组研究结果有力地表明，氟西汀在海马区诱导神经发生有助于氟西汀的行为效应。下面的实验旨在验证这一假设，并建立成人海马神经发生的功能意义。

DESCRIPTION (provided by applicant): The current proposal is aimed at understanding the mode of action of medications that are currently used to treat a variety of depression and anxiety-related disorders. Although selective serotonin reuptake inhibitors (SSRI) are the most commonly prescribed antidepressants and anxiolytics, their mechanisms of action, and particularly the reason for their delayed (4-6 weeks) onset of therapeutic effects, are largely unknown. The general hypothesis that we are proposing to test is that the increased hippocampal neurogenesis elicited by chronic antidepressants contributes to the behavioral effects of these drugs. We, and others, have shown that various chronic antidepressant treatments result in an increase in neurogenesis in the dentate gyrus of the hippocampus. We have also shown that a chronic antidepressant treatment decreases certain anxiety-related behavioral responses. Finally, we have developed two distinct manipulations (a genetic one and radiological one) that disrupt antidepressant-induced hippocampal neurogenesis and also suppress antidepressant-induced behavioral responses. The genetic manipulation is a deletion of the gene encoding the 5-HT1A receptor; the resulting knockout mice are insensitive to the effects of SSRIs such as fluoxetine on both neurogenesis and behavior. The radiological manipulation consists of an X-irradiation of an area of the mouse brain containing the hippocampus; such a treatment prevents the effect of fluoxetine on both neurogenesis and behavior. These two sets of findings strongly suggest that the induction of neurogenesis elicited by fluoxetine in the hippocampus contributes to the behavioral effects of fluoxetine. The following experiments are designed to test this hypothesis and to establish the functional significance of adult hippocampal neurogenesis. 1. We will test the hypothesis that activation of hippocampal 5-HTIA receptors mediates the effects of fiuoxetine on neurogenesis and behavior. To accomplish this goal, we will construct "rescue" mice that express 5-HT1A receptors only in the hippocampus. 2. We will test the hypothesis that an ablation of neuronal progenitors will suppress the effects of fluoxetine. Such a finding would open new therapeutic avenues based on the stimulation of hippocampal neurogenesis, for the treatment of depression-related disorders.