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

描述（由申请人提供）：目前尚不清楚是什么因素使某些人容易患上重度抑郁症，这是一种慢性严重疾病，对个人、家庭乃至社会造成严重损害。我的长期目标是了解赋予复发性抑郁症特质易感性的生物学易感性因素。为了实现这一长期目标，我在英国牛津大学收集了易患抑郁症的个体的数据，使用了正电子发射断层扫描（PET）、磁共振波谱（MRS）和神经内分泌分析的组合。使用这些方法，我已经引起了被认为是抑郁症病理生理学基础的系统的异常，包括血清素（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，使某些人容易患抑郁症的关键因素不是个体生物系统中孤立的异常，而是这些系统的不适应相互作用。我的初步数据显示，用磁共振波谱（MRS）测量的皮质GABA水平存在持久的缺陷，这与情绪状态和之前的治疗无关，在经历过复发性抑郁症的个体中。我也证明了具有5-羟色胺转运体多态性（5-HTTPRL） s等位基因的健康对照个体具有较低的皮质GABA水平。初步数据还表明，具有5-HTTPRL基因s等位基因的个体更有可能在色氨酸耗竭后抑郁症状复发。我建议研究这些关键系统的相互作用。本提案的具体目标是：1。研究5-羟色胺系统是否是与抑郁易感性相关的GABA缺陷的关键介质。2. 测试抑郁症易感性的分子模型。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，研究急性色氨酸耗损对完全康复、身心健康、无药物治疗且有复发性重度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多态性对皮质GABA的影响。2.1还将在实验1中对完全康复、心境平和、无药物治疗且有复发性重度抑郁症病史的受试者进行随访，以确定2年内复发的受试者与未复发的受试者相比，皮质GABA是否较低。相关性：抑郁症是一种常见而严重的疾病，被认为是大脑化学物质功能障碍的结果。利用复杂的脑成像技术和基因分析，该项目将研究导致抑郁症的两种主要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.