Cellular Mechanisms of Antidepressant Action

说明(申请人提供)：大多数抗抑郁药有延迟的治疗效果。具体地说，SSRIs和三环类抗抑郁药通常需要几周的服药时间才能达到完全的临床疗效。解释这种延迟的两个主要假设是：1：自身受体如5-HT1A和5-HT1B自身受体的渐进性脱敏，最初限制了大多数抗抑郁药产生的5-羟色胺的增加；2：这些药物引起的单胺增加的下游可能发生的生长相关变化。在这些与生长相关的事件中，大部分焦点都集中在海马体和其他边缘结构(如杏仁核和前额叶皮质)中的树突生长，以及海马区新神经元的生成，这一现象被称为神经发生。在之前的资助期间，我们开发了三种对慢性但不是急性抗抑郁药物有反应的动物模型：新奇抑制进食、新奇诱导的吞噬减少和慢性不可预测的应激范例。此外，我们还开发了新的遗传策略，有条件地去除5-HT1A自身受体和年轻的海马神经元。在这次竞争性更新中，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：我们将检验这样一个假设，即缺乏5-HT1A和/或5-HT1B自身受体的小鼠对抗抑郁药物的反应会更快。目的2：我们将检验这一假设，即年轻的海马神经元是抗抑郁药物的行为效应所必需的。目的3：我们将尝试确定5-羟色胺受体，这些受体负责SSRIs对神经发生和行为的影响。具体地说，我们将测试这一假设，即位于海马祖细胞上的5-HT1a受体对于慢性氟西汀对神经发生和可能对行为的影响是必要的。因此，这一提议可能会为开发直接针对神经发生或模仿年轻海马神经元特性的新型抗抑郁药物提供思路。由于神经发生的解剖学特异性，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.