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5-羟色胺（5-羟色胺，5-HT）神经传递的改变在精神疾病，特别是抑郁症的发病机制中起重要作用。这一理论源于药物（例如，增加细胞外5-HT（5-HTExt）水平的SSRIs治疗抑郁症具有中等疗效，并且在抑郁症中反复报道了中枢5-HT功能的假定“生物标志物”异常。然而，脑5-HT功能障碍从来没有被直接证明在抑郁症患者和低5-HT是否可以引起或易患抑郁症仍然不清楚。脑5-HT合成的限速步骤是色氨酸羟化酶2（Tph 2）将色氨酸转化为5-羟色氨酸（5-HTP）。最近发现的功能性突变的几个基因参与5-羟色胺稳态，包括tph 2，和他们的协会与抑郁症或受损的治疗反应SSRIs刺激抑郁症的5-羟色胺缺乏理论的新兴趣。我们已经产生了一种携带罕见的Tph 2（R439 H）突变的小鼠品系，该突变最初在抑郁症队列中被鉴定。在这些突变小鼠中，脑5- HT合成和组织储存减少了80%，5-HTExt水平减少了60- 80%，而诱发的5-HTExt反应被定性地保留。小鼠重现了严重抑郁症中报告的推定5-HT生物标志物的几种异常，并表现出抑郁、焦虑和攻击性行为，似乎提供了与人类5-HT缺陷相关的行为改变模型。因此，我们的突变（以下简称5-HTypo）小鼠可能代表了一个独特的自然模型5-HT缺乏症，并可能，抑郁症。可能的是，对5-HT体内平衡的多种不同的损伤可以各自导致5-HT缺乏，因此5-HThypo小鼠可能代表了一般5-HT缺乏的有用模型以及受损的Tph 2催化功能的模型。我们继续研究的总体目标是使用5-HThypo小鼠更好地了解5-HT缺乏如何导致抑郁症病因并影响抗抑郁药治疗，包括应激易感性的后果以及对当前和新疗法的反应。为此，我们提出了四个具体目标。目标1将确定5-HT缺乏是否会改变对压力的敏感性， 在社交失败和慢性轻度压力的范例中。目的2将测试是否SSRI和氯胺酮的抗抑郁样反应受到5-HT缺乏的影响。目标3将在5-HT缺乏和正常条件下临床前测试一种新的基于5-HT的抗抑郁药增强概念。在目标4中，我们将使用传统的和国家的最先进的方法，以确定潜在的抑郁样行为所产生的5-HT缺乏的细胞信号通路的变化。总的来说，拟议的实验将解决抑郁症神经生物学中长期悬而未决的问题，并测试一种新的治疗概念。