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

描述(由申请人提供)：尚不清楚是什么因素使某些人容易患上严重的抑郁症，这是一种慢性、严重的疾病，对个人、他们的家庭以及最终对社会造成严重损害。我的长期目标是了解导致特征易患复发性抑郁障碍的生物脆弱性因素。为了这个长期目标，我在英国牛津大学收集了易患抑郁症的人的数据，使用正电子发射断层扫描(PET)、磁共振波谱(MRS)和神经内分泌分析相结合的方法。使用这些方法，我已经在被认为是抑郁症病理生理学基础的系统中引起了异常，包括5-羟色胺(5-HT)系统、下丘脑垂体肾上腺轴(HPA)和皮质伽马氨基丁酸(GABA)。然而，我认为，使某些人容易患抑郁症的关键因素不是单个生物系统中的孤立异常，而是这些系统的不适应相互作用。我的初步数据显示，在经历过反复抑郁症的个人中，用磁共振波谱(MRS)测量的皮质GABA水平存在持久的缺陷，这与情绪状态和先前的治疗无关。我还证明了具有5-羟色胺转运体多态(5-HTTPRL)S等位基因的健康对照组个体皮质GABA水平较低。初步数据还表明，具有5-HTTPRL经验的S等位基因的个体更有可能在色氨酸耗竭后经历抑郁症状的复发。我建议研究这些关键系统之间的相互作用。这项建议的具体目的是：1.研究5-羟色胺系统是否是与抑郁易感性相关的GABA缺陷的关键中介。2.测试抑郁症易感性的分子模型。设计：我将进行两个实验。1.1建议采用安慰剂对照、平衡顺序、双盲设计，研究急性色氨酸耗竭对完全康复、心境良好、无药物史、有重复性抑郁症病史的受试者皮质GABA水平的影响。每组中的受试者也将被研究，以确定5-HTTPRL的多态对皮质GABA的影响。2.1还将在实验1中对完全康复、情绪良好、无药物治疗、有重复性抑郁症病史的受试者进行跟踪调查，以确定复发超过2年的受试者与未复发的受试者相比，皮质GABA是否较低。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。该项目将利用复杂的大脑成像技术和基因分析，研究两种主要大脑化学物质之间的相互作用，这两种化学物质与抑郁症的原因有关。

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.