The Effects of 5-HT Deficiency on Responses to Stress and Antidepressant Drugs

5-HT 缺乏对压力和抗抑郁药物反应的影响

• 批准号: 8217310
• 负责人: Benjamin D Sachs
• 金额: $ 5.39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8217310
• 关键词: Acute; Address; Adult; Age; Agonist; American; Animals; Antidepressive Agents; Anxiety; Attenuated; Behavior; Behavioral; Biological; Biological Process; Brain; Cells; Chronic; Chronic stress; Clinical; Data; Depressed mood; Development; Disease remission; Disease susceptibility; Enzymes; Evaluation; Exhibits; Fenfluramine; Functional disorder; Genes; Genetic; Hippocampus (Brain); Human; Hydroxyindoleacetic Acid; Immunohistochemistry; Individual; Knock-in Mouse; Laboratories; Lead; Light; Major Depressive Disorder; Measures; Mental Depression; Morbidity - disease rate; Mus; Mutation; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Population; Predisposing Factor; Preparation; Prolactin; Regulation; Research; Rodent; Rodent Model; Selective Serotonin Reuptake Inhibitor; Series; Serotonin; Serotonin Receptor 5-HT1A; Stress; System; Testing; Tissues; Tryptophan 5-monooxygenase; Work; adult neurogenesis; base; behavior test; behavioral pharmacology; cohort; depressive symptoms; disability; extracellular; improved; meetings; mortality; mouse Tph2 protein; mouse model; mutant; nerve stem cell; neurogenesis; neurotransmission; novel; pre-clinical; prevent; public health relevance; research study; resilience; response; stress resilience; theories

DESCRIPTION (provided by applicant): Major depression is the leading cause of disability among Americans between the ages of 15 and 44 and is one of the top ten causes of morbidity and mortality worldwide. Current treatments are well tolerated but can lead to less than 50% remission rates among patients. Due to the fact that most antidepressant drugs act by increasing extracellular levels of serotonin (5-HT), it has been hypothesized that decreased levels of 5-HT might underlie major depressive illness. However, this theory has been difficult to test in a preclinical setting due to a lack of hyposerotonergic mouse models. The tryptophan hydroxylase 2 R439H knock-in mouse (Tph2KI) provides a novel system in which the consequences of chronic 5-HT deficiency can be examined. This mouse exhibits an 80% reduction in brain 5-HT as the result of a mutation in Tph2, the enzyme responsible for brain 5-HT synthesis. In addition, these mice recapitulate several physiological features often associated with depression, including inhibited prolactin secretion and hypothermic responses to serotonergic activation, and decreased levels of the 5-HT metabolite, 5-HIAA. Because of these physiologic parallels to the human condition, Tph2KI mice represent a highly relevant, naturalistic rodent model for studying the impact of low levels of 5-HT on cell biological processes and behaviors related to depression and antidepressant action. Work from the past decade has demonstrated that elevation of 5-HT promotes neurogenesis and has revealed a requirement for neurogenesis in several antidepressant-like effects in mice. Elevation of 5-HT using antidepressant drugs can also prevent the inhibition of neurogenesis and the depressive-like behaviors induced by exposure of rodents to chronic stress. However, whether decreased levels of 5-HT lead to impaired neurogenesis, altered antidepressant-like responses, or increased vulnerability to stress has not been determined. The proposed research will test the hypothesis that chronic 5-HT deficiency will lead to inhibition of baseline adult hippocampal neurogenesis, diminished responses to antidepressant drugs, and decreased resilience to chronic stress. This hypothesis will be evaluated through the performance of three specific aims: 1) To examine the effects of hyposerotonergia on baseline hippocampal neurogenesis. 2) To determine the neurogenic and behavioral responses of 5-HT deficient mice to antidepressants. 3) To study the neurogenic and behavioral consequences of chronic stress in Tph2KI mice. These experiments will provide some of the first experimental evidence regarding the impact of chronic hyposerotonergia on adult neurogenesis, antidepressant responses, and vulnerability to stress. The data obtained from the proposed study will address several prominent depression theories, including the Serotonin Deficiency, the Neurogenesis Deficiency, and the Diathesis-Stress Hypotheses of depression and may shed light on the pathophysiology underlying depressive-like states. PUBLIC HEALTH RELEVANCE: Drugs that enhance serotonin neurotransmission are known to stimulate neurogenesis and are the primary pharmacotherapy in the treatment of major depression (MD), which is the leading cause of disability among Americans between the ages of 15 and 44. However, it has not been definitively proven whether serotoninergic or neurogenic dysfunctions exist in MD, or whether these deficiencies are sufficient to cause MD. The proposed research will evaluate the behavioral and cell biological (i.e. neurogenic) consequences of hyposerotonergia in mice and will enhance our understanding of the mechanisms underlying depressive-like behaviors and antidepressant-like responses.

描述（由申请人提供）：重度抑郁症是 15 岁至 44 岁美国人残疾的主要原因，也是全球发病率和死亡率的十大原因之一。目前的治疗方法耐受性良好，但患者的缓解率低于 50%。由于大多数抗抑郁药物通过增加细胞外血清素 (5-HT) 水平发挥作用，因此推测 5-HT 水平降低可能是重度抑郁症的基础。然而，由于缺乏血清素能过低的小鼠模型，这一理论很难在临床前环境中进行检验。色氨酸羟化酶 2 R439H 敲入小鼠 (Tph2KI) 提供了一种新的系统，可以在其中检查慢性 5-HT 缺乏的后果。由于 Tph2（负责大脑 5-HT 合成的酶）发生突变，该小鼠的大脑 5-HT 减少了 80%。此外，这些小鼠重现了一些通常与抑郁症相关的生理特征，包括催乳素分泌受到抑制和对血清素激活的低温反应，以及 5-HT 代谢物 5-HIAA 水平降低。由于这些生理学与人类状况相似，Tph2KI 小鼠代表了一种高度相关的自然啮齿动物模型，用于研究低水平 5-HT 对与抑郁和抗抑郁作用相关的细胞生物过程和行为的影响。过去十年的研究表明，5-HT 升高可促进神经发生，并揭示了小鼠体内几种抗抑郁样作用需要神经发生。使用抗抑郁药物升高 5-HT 还可以防止神经发生的抑制以及啮齿类动物因长期应激而诱发的抑郁样行为。然而，5-HT 水平降低是否会导致神经发生受损、抗抑郁样反应改变或对压力的脆弱性增加尚未确定。拟议的研究将检验以下假设：慢性 5-HT 缺乏将导致成人海马神经发生基线受到抑制、对抗抑郁药物的反应减弱以及对慢性压力的恢复能力下降。该假设将通过三个具体目标的表现进行评估：1）检查血清素低下对基线海马神经发生的影响。 2) 确定5-HT缺陷小鼠对抗抑郁药的神经源性和行为反应。 3) 研究Tph2KI小鼠慢性应激的神经源性和行为后果。这些实验将提供一些关于慢性血清素低下对成人神经发生、抗抑郁反应和压力脆弱性影响的初步实验证据。从拟议的研究中获得的数据将解决几个重要的抑郁症理论，包括血清素缺乏症、神经发生缺乏症和抑郁症的素质-压力假说，并可能揭示抑郁样状态背后的病理生理学。 公共健康相关性：已知增强血清素神经传递的药物可以刺激神经发生，并且是治疗重度抑郁症 (MD) 的主要药物疗法，重度抑郁症是 15 岁至 44 岁之间美国人残疾的主要原因。尚未明确证明 MD 是否存在血清素能或神经源性功能障碍，或者这些缺陷是否足以导致 MD。拟议的研究将评估小鼠血清素能低下的行为和细胞生物学（即神经源性）后果，并将增强我们对抑郁样行为和抗抑郁样反应背后机制的理解。