A study of GABA and 5-HT interactions to test a molecular model of vulnerability

描述（由申请人提供）：目前还不清楚是什么因素使某些人容易患上严重抑郁症，这是一种慢性严重疾病，对个人、家庭和最终社会造成严重影响。我的长期目标是了解赋予复发性抑郁症特质脆弱性的生物脆弱性因素。有了这个长期的目标，我收集了数据的个人容易抑郁症在牛津大学，英国，使用正电子发射断层扫描（PET），磁共振波谱（MRS）和神经内分泌测定相结合。使用这些措施，我已经引起异常的系统被认为是基本的病理生理学抑郁症，包括5-羟色胺（5-HT）系统，下丘脑垂体肾上腺轴（HPA）和皮质γ-氨基丁酸（GABA）。然而，我相信，使某些人容易患上抑郁症的关键因素不是个体生物系统中的孤立异常，而是这些系统的适应不良相互作用。我的初步数据显示，在经历过复发性抑郁症的个体中，用磁共振波谱（MRS）测量的皮质GABA水平存在持久的缺陷，这与情绪状态和既往治疗无关。我还证明了健康对照组中5-HT转运蛋白多态性（5-HTTPRL）的s等位基因具有较低的皮质GABA水平。初步数据还表明，具有5-HTTPRL经历的s等位基因的个体更有可能在色氨酸耗尽后经历抑郁症状的复发。我建议研究这些关键系统的相互作用。该提案的具体目标是1。研究5-HT系统是否是GABA缺乏与抑郁易感性相关的关键介质。2.去测试易患抑郁症的分子模型。设计：我将做两个实验。1.1拟采用安慰剂对照、平衡顺序、双盲设计，研究急性色氨酸耗竭对质子MRS测量的皮质GABA水平的影响，受试者为完全恢复、情绪正常、无药物治疗且有复发性重度抑郁症病史的受试者。还将研究每组中的受试者以确定5-HTTPRL多态性对皮质GABA的影响。2.1还将随访在实验1中具有复发性重性抑郁症病史的完全康复的、情绪正常的、无药物治疗的受试者的队列，以确定与未复发的受试者相比，复发超过2年的受试者是否具有较低的皮质GABA。相关性：抑郁症是一种常见的严重疾病，被认为是大脑化学物质功能障碍的结果。利用先进的大脑成像技术和遗传分析，该项目将研究与抑郁症病因有关的两种主要大脑化学物质的相互作用。

DESCRIPTION (provided by applicant): It is unclear what factors make certain individuals vulnerable to episodes of major depression, a chronic, severe illness which levies a crippling toll on the individual, their family and eventually society. My long term objective is to understand the biological vulnerability factors that confer trait vulnerability to recurrent depressive disorder. With this long term objective, I have gathered data on individuals vulnerable to depression at the University of Oxford, UK, using a combination of positron emission tomography (PET), magnetic resonance spectroscopy (MRS) and neuroendocrine assays. Using these measures I have elicited abnormalities in systems considered fundamental to the pathophysiology to depression including the serotonin (5-HT) system, the hypothalamic pituitary adrenal axis (HPA) and cortical gamma amino butyric acid (GABA). However, I believe that the critical factor which makes certain individuals vulnerable to depression is not an isolated abnormality in an individual biological system but is a maladaptive interaction of these systems. My preliminary data show that there is an enduring deficit in cortical GABA levels measured with magnetic resonance spectroscopy (MRS), which is independent of mood state and prior treatment, in individuals who have experienced recurrent depressive illness. I have also demonstrated that healthy control individuals with an s allele of the 5-HT transporter polymorphism (5-HTTPRL) have lower cortical GABA levels. Preliminary data also suggests that individuals with the s allele of the 5-HTTPRL experience are more likely to experience a relapse of depressive symptoms following tryptophan depletion. I propose to study the interactions of these critical systems. The specific aims for this proposal are 1. To study whether the 5-HT system is a critical mediator of the GABA deficits associated with vulnerability to depression. 2. To test a molecular model of vulnerability to depression. Design: I will perform two experiments. 1.1 propose to study the effect of acute tryptophan depletion on cortical GABA levels measured by proton MRS in fully recovered, euthymic, medication free subjects with a history of recurrent major depressive disorder in a placebo controlled, balanced order, double blind design. Subjects within each group will also be studied to determine the effect of polymorphisms of the 5-HTTPRL on cortical GABA. 2.1 will also follow up the cohort of fully recovered, euthymic, medication free subjects with a history of recurrent major depressive disorder in experiment 1 ,'to determine whether subjects who relapse over 2 years have lower cortical GABA compared with subjects who do not relapse. Relevance: Depression is a common and severe illness which is thought to occur as a result of a dysfunction of brain chemicals. Using sophisticated brain imaging techniques and genetic analysis, this project will study the interaction of two main brain chemicals implicated in the causation of depression.