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疗效。特别是SSRIs和三环类抗抑郁药通常需要几周的给药才能达到完全的临床疗效。已经提出的解释这种延迟的两个主要假设是：1：自身受体如5-HT 1A和5-HT 1B自身受体的渐进脱敏，其最初限制大多数抗抑郁药产生的5-羟色胺的增加，和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。在这些与生长有关的事件中，大部分的焦点集中在海马和其他边缘结构（如杏仁核和前额皮质）中的树突生长，以及海马中新神经元的产生，这种现象称为神经发生。我们已经在前一个资助期开发了三种动物模型，对慢性抗抑郁药有反应，但对急性抗抑郁药无反应：新奇抑制喂养，新奇诱导的食欲减退和慢性不可预测的应激范式。此外，我们已经开发了新的遗传策略，有条件地消融5-HT 1A自身受体以及年轻的海马神经元。在这种竞争性的更新中，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-HT 1A和/或5-HT 1B自身受体的小鼠对抗抑郁药的反应更快的假设。目的2：我们将测试的假设，年轻的海马神经元是必要的抗抑郁药的行为效应。目的3：我们将试图确定5-HT受体，这是负责SSRIs对神经发生和行为的影响。具体来说，我们将测试的假设，5-HT 1A受体位于海马祖细胞是必要的慢性氟西汀对神经发生的影响，并可能对行为。因此，这一提议可能为直接靶向神经发生或模仿年轻海马神经元特性的新型抗抑郁药的产生提供思路。由于神经发生的解剖学特异性，除了更快的疗效起效之外，预期此类药物可能具有更少的副作用。

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.