The 5-HT theory of depression tested in a naturalistic model of 5-HT deficiency

在 5-HT 缺乏的自然模型中测试的 5-HT 抑郁理论

• 批准号: 8895461
• 负责人: Marc G. Caron
• 金额: $ 10万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-11 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895461
• 关键词: 5-Hydroxytryptophan; Acute; Address; Affect; Amygdaloid structure; Animal Model; Antidepressive Agents; Anxiety; Behavior; Behavioral; Behavioral Model; Biochemical; Biological Markers; Brain; Chronic; Clinical; Data; Depressive Syndromes; Development; Disease; Etiology; Exhibits; Foundations; Functional disorder; Genes; Genetic Engineering; Glutamates; Goals; Homeostasis; Human; Ketamine; Lead; Mediating; Mental Depression; Mental disorders; Modeling; Molecular; Mood Disorders; Mus; Mutant Strains Mice; Mutation; Neurobiology; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Preclinical Testing; Predisposition; Psyche structure; Publishing; Reporting; Research; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Pathway; Signal Transduction; Stress; Symptoms; System; Testing; Therapeutic; Tissues; Tryptophan; Tryptophan 5-monooxygenase; Work; base; cohort; extracellular; frontal lobe; improved; indexing; insight; interest; mood regulation; mouse model; mutant; neurochemistry; neurotransmission; novel; novel therapeutic intervention; psychobiologic; research clinical testing; research study; response; social; stem; stressor; theories; tool; treatment-resistant depression

DESCRIPTION (provided by applicant): Alterations in serotonin (5-hydroxytryptamine, 5-HT) neurotransmission have long been theorized to play an important role in the pathogenesis of psychiatric disorders, particularly depression. This theory stems from the facts that drugs (e.g., SSRIs) increasing levels of extracellular 5-HT (5-HTExt) treat depression with moderate efficacy and that anomalies in putative "biomarkers" of central 5-HT function have been repeatedly reported in depression. However, brain 5-HT dysfunction has never been directly demonstrated in depression patients and whether low 5-HT can elicit or predispose to depression remains unclear. The rate-limiting step in brain 5-HT synthesis is the conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase 2 (Tph2). The recent identification of functional mutations in several of the genes involved in 5-HT homeostasis, including tph2, and their associations with depression or impaired therapeutic responses to SSRIs have stimulated renewed interest in the 5-HT deficiency theory of depression. We have generated a mouse line carrying a rare Tph2(R439H) mutation originally identified in a depression cohort. In these mutant mice brain 5- HT synthesis and tissue storage are decreased by 80% and 5-HTExt levels by 60-80%, while evoked 5-HTExt responses are qualitatively preserved. The mice recapitulate several anomalies in putative 5-HT biomarkers reported in severe depression and exhibit depression-, anxiety-, and aggressive-like behaviors, seemingly providing a model of the behavioral alterations associated with 5-HT deficits in humans. Thus, our mutant (henceforth 5-HThypo) mice may represent a unique naturalistic model of 5-HT deficiency and, possibly, depression. Plausibly, multiple diverse insults to 5-HT homeostasis could each result in 5-HT deficiency, thus the 5-HThypo mouse likely represents a useful model of 5-HT deficiency in general as well as a model of impaired Tph2 catalytic function. The overall goal of our continued research is to use the 5-HThypo mouse to better understand how 5-HT deficiency contributes to depression etiology and affects antidepressant treatment, including the consequences for stress susceptibility and responses to current and novel therapies. For this goal, we propose four specific aims. Aim 1 will define whether 5-HT deficiency alters susceptibility to stress, as tested in the social defeat and chronic mild stress paradigms. Aim 2 will test whether antidepressant- like responses to SSRI and ketamine are affected by 5-HT deficiency. Aim 3 will pre-clinically test a novel 5- HTP-based antidepressant augmentation concept under 5-HT-deficient and normal conditions. In Aim 4 we will use conventional and state-of-the-art approaches to identify the cellular signaling pathway changes underlying the depression-like behaviors arising consequent to 5-HT deficiency. Collectively, the proposed experiments will address long outstanding questions in depression neurobiology and test a new treatment concept.

描述（由申请人提供）：长期以来，理论上将羟色胺（5-羟色胺，5-HT）神经传递的变化在精神疾病的发病机理中起着重要作用，尤其是抑郁症。该理论源于以下事实：在抑郁症中反复报道了在抑郁症中反复报道的药物（例如SSRIS）增加了细胞外5-HT（5-HTEXT）治疗抑郁症的水平，并且在中央5-HT功能的假定“生物标志物”中的异常。然而，在抑郁症患者中从未直接证明大脑5-HT功能障碍，而低5-HT是否会引起或易感抑郁症仍不清楚。大脑5-HT合成中的速率限制步骤是色氨酸转化为色氨酸羟化酶2（TPH2）的5-羟色属pophan（5-HTP）。包括TPH2在内的5-HT稳态涉及的几个基因中的功能突变及其与抑郁症或对SSRIS的治疗反应受损的关联的鉴定，已经激发了对5-HT缺乏抑郁理论的重新兴趣。我们已经产生了一条携带罕见的TPH2（R439H）突变的小鼠系，最初在抑郁症队列中鉴定出来。在这些突变小鼠中，脑5-HT合成，组织储存的80％和5-HTEXT水平降低了60-80％，而诱发的5-HTEXT响应是定性保留的。小鼠概括了在严重抑郁症中报道的假定的5-HT生物标志物中的几个异常情况，并且表现出抑郁症，焦虑和侵略性行为，似乎提供了与人类5-HT缺陷有关的行为改变的模型。因此，我们的突变体（此后5-HTHYPO）小鼠可能代表了5-HT缺乏症和可能是抑郁症的独特自然主义模型。合理地，对5-HT稳态的多种侮辱可能会导致5-HT缺乏，因此，5-HTHYPO小鼠通常代表了通常的5-HT缺乏症的有用模型，以及TPH2催化功能受损的模型。我们持续研究的总体目标是使用5-HTHYPO小鼠更好地了解5-HT缺乏症如何促进抑郁症病因并影响抗抑郁药的治疗，包括对压力敏感性以及对当前和新型疗法的反应的后果。对于这个目标，我们提出了四个具体目标。 AIM 1将定义5-HT缺乏是否改变了对压力的敏感性，如测试 在社交失败和慢性轻度压力​​范式中。 AIM 2将测试对SSRI和氯胺酮的抗抑郁药反应是否受到5-HT缺乏的影响。 AIM 3将在5-HT缺乏和正常条件下进行临时测试一种新型的5-HTP抗抑郁药增强概念。在AIM 4中，我们将使用常规和最先进的方法来识别5-HT缺乏造成的类似抑郁行为的细胞信号通路发生变化。总的来说，拟议的实验将解决抑郁症神经生物学中的长期杰出问题，并测试新的治疗概念。