Cellular Mechanisms of Antidepressant Action

描述（由申请人提供）：大多数抗抑郁药具有延迟起效的治疗效果。特别是SSRIs和三环类抗抑郁药通常需要几周的服用才能达到完全的临床疗效。为了解释这种延迟，人们提出了两个主要假设：1 .自体受体（如5-HT1A和5-HT1B自体受体）的逐渐脱敏，它们最初限制了大多数抗抑郁药产生的血清素的增加；2 .生长相关的变化可能发生在这些药物引起的单胺增加的下游。在这些与生长相关的事件中，大部分焦点集中在海马体和其他边缘结构（如杏仁核和前额叶皮层）的树突生长，以及海马体中新神经元的产生，这种现象被称为神经发生。在之前的资助期内，我们已经开发了三种对慢性而非急性抗抑郁药有反应的动物模型：新奇抑制的喂养，新奇诱导的吞咽不足和慢性不可预测的应激范式。此外，我们还开发了新的遗传策略来有条件地消融5-HT1A自身受体以及年轻的海马神经元。在这种竞争性更新中，我们建议利用这些行为和遗传工具来实现以下目标：目标1：我们将测试缺乏5-HT1A和/或5-HT1B自受体的小鼠对抗抑郁药的反应更快的假设。目的2：我们将检验年轻的海马神经元对抗抑郁药的行为影响是必要的假设。目标3：我们将尝试确定负责SSRIs对神经发生和行为影响的5-HT受体。具体来说，我们将验证位于海马祖细胞上的5-HT1A受体是慢性氟西汀对神经发生和行为的影响所必需的假设。因此，这一建议可能为产生新的抗抑郁药提供了思路，这些抗抑郁药将直接针对神经发生或模仿年轻海马神经元的特性。由于神经发生的解剖特异性，这类药物可能会有更少的副作用，以及更快的治疗效果。

DESCRIPTION (provided by applicant): Most antidepressants have a delayed onset of therapeutic efficacy. Specifically SSRIs and tricyclic antidepressants often require several weeks of administration to reach full clinical efficacy. The two main hypotheses which have been proposed to explain this delay is 1: a progressive desensitization of autoreceptors such as the 5-HT1A and 5-HT1B autoreceptors which initially limit the increase in serotonin produced by most antidepressants, and 2: growth related changes that may take place downstream of the increases in monoamines elicited by these drugs. Among these growth-related events much of the focus has been on dendritic growth in the hippocampus and other limbic structures such as the amygdala and the prefrontal cortex, and on the generation of new neurons in the hippocampus, a phenomenon termed neurogenesis. We have developed in the previous funding period three animal models that respond to chronic but not acute antidepressants: the novelty-suppressed feeding, novelty-induced hypophagia and chronic unpredictable stress paradigms. In addition we have developed new genetic strategies to conditionally ablate 5-HT1A autoreceptors as well as young hippocampal neurons. In this competitive renewal we propose to take advantage of these behavioral and genetic tools to accomplish the following goals: Aim 1: We will test the hypothesis that mice lacking the 5-HT1A and/or the 5-HT1B autoreceptors will respond faster to antidepressants. Aim 2: We will test the hypothesis that young hippocampal neurons are necessary for the behavioral effects of antidepressants. Aim 3: We will attempt to identify the 5-HT receptors which are responsible for the effects of SSRIs on neurogenesis and behavior. Specifically, we will test the hypothesis that 5-HT1A receptors located on hippocampal progenitors are necessary for the effects of chronic fluoxetine on neurogenesis and possibly on behavior. This proposal may therefore provide ideas for the generation of novel antidepressants that would directly target neurogenesis or mimic the properties of young hippocampal neurons. Due to the anatomic specificity of neurogenesis, such agents might be expected to have fewer side effects, in addition to a faster onset of therapeutic efficacy.