Cellular Mechanisms of Antidepressant Action

抗抑郁作用的细胞机制

• 批准号: 8046423
• 负责人: Rene Hen
• 金额: $ 39.58万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-07 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046423
• 关键词: Ablation; Acute; Adult; Adverse effects; Amygdaloid structure; Anatomy; Animal Model; Animals; Antidepressive Agents; Autoreceptors; Behavior; Behavioral; Behavioral Genetics; Chronic; Desipramine; Event; Fluoxetine; Funding; Generations; Genetic; Goals; Growth; Hippocampus (Brain); Lead; Modeling; Mus; Neuroglia; Neurons; Pharmaceutical Preparations; Prefrontal Cortex; Property; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT1A; Specificity; Stress; Structure; Testing; Treatment Efficacy; Tricyclic Antidepressive Agents; behavior test; clinical efficacy; desensitization; feeding; monoamine; neurogenesis; novel; progenitor; receptor; response; tool

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.

描述（由申请人提供）：大多数抗抑郁药的治疗效果起效较晚。特别是 SSRIs 和三环类抗抑郁药通常需要服用数周才能达到完全的临床疗效。提出来解释这种延迟的两个主要假设是 1：自身受体（例如 5-HT1A 和 5-HT1B 自身受体）逐渐脱敏，最初限制了大多数抗抑郁药产生的血清素的增加；2：与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（如杏仁核和前额皮质）的树突生长，以及海马体中新神经元的生成，这种现象称为神经发生。我们在上一个资助期间开发了三种动物模型，它们对慢性而非急性抗抑郁药有反应：新奇抑制进食、新奇引起的吞咽不足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：我们将测试以下假设：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。目标 2：我们将检验这一假设：年轻的海马神经元对于抗抑郁药的行为作用是必要的。目标 3：我们将尝试识别 5-HT 受体，它们负责 SSRIs 对神经发生和行为的影响。具体来说，我们将检验以下假设：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以及可能对行为的影响是必需的。因此，该提议可能为产生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提供思路。由于神经发生的解剖学特异性，除了更快起效之外，此类药物的副作用可能也更少。