Early Stress, PTSD, and the Neurobiology of Addiction

童年时期反复受到压力和创伤会产生一连串的分子和细胞事件，有可能对大脑发育产生持久的影响。这些变化可能导致抑郁症、创伤后应激障碍(PTSD)的发展，以及对药物使用和成瘾的易感性增加。研究1将检验以下假设：创伤后应激障碍和反复发作的抑郁症都在儿童创伤应激和药物滥用风险增加之间起中介作用。这项研究还将测试 假设MAO-A启动子的功能多态产生低水平的MAO-A活性将与儿童创伤应激对药物使用的不利影响的易感性增加相关。这些假设将在20-25岁的样本(n=500)中进行检验，这些人要么没有童年虐待史，要么有童年虐待史，符合创伤后应激障碍的A(1)A(2)标准。研究2将测试以下假设：暴露于慢性儿童创伤应激会影响小脑蠕虫的形态、神经元完整性和顺磁性，以及小脑蠕虫异常将与药物滥用风险增加相关。从第一项研究中将确定三组受试者(每组30人)。受试者将有：(1)没有儿童虐待创伤史；(2)儿童创伤应激和创伤后应激障碍；或(3)儿童创伤应激和反复发作的严重抑郁。三组中的受试者将在物质使用程度上进行匹配。形态磁共振成像、T2弛豫测量和质子回波平面光谱成像将用于验证这些假说。这些受试者还将接受探测剂量的哌甲酸甲酯和重复的T2-RT扫描，以检验以下假设：暴露于童年创伤应激可以增强纹状体和小脑虫对刺激性药物的血流动力学反应。研究3将在特里尔社会压力测试中检验以下假设：暴露在儿童创伤应激环境中会产生更强、更持久的促肾上腺皮质激素、去甲肾上腺素和加压素反应(以及减少或延迟的催产素反应)。总体而言，这些研究将为我们提供对 儿童慢性创伤应激的神经生物学效应，以及对创伤后应激和抑郁的潜在调节作用的新认识，以及MAO-A水平的适度，早期应激与药物滥用之间的关联。这些研究还将探索新的假设，即压力导致的小脑蠕虫改变和催产素释放与慢性儿童创伤应激幸存者的药物滥用风险有关。

Exposure to repeated stress and trauma during childhood produces a cascade of molecular and cellular events that has the potential to exert enduring effects on brain development. These changes may be responsible for the development of depression, posttraumatic stress disorder (PTSD) and increased vulnerability to substance use and addiction. Study 1 will test the hypotheses that both PTSD and recurrent major depression mediate the association between childhood traumatic stress and increased risk for substance abuse. This study will also test the hypothesis that a functional polymorphism in the MAO-A promoter, which produces low levels of MAO-A activity will be associated with increased vulnerability to the adverse effects of childhood traumatic stress on drug use. These hypotheses will be tested in a sample of 20-25 year olds (n=500) who either have no history of exposure to childhood abuse or who have had a history of exposure to childhood abuse that fulfills the A(1) A(2) criteria for PTSD. Study 2 will test the hypotheses that exposure to chronic childhood traumatic stress effects the morphology, neuronal integrity and paramagnetic properties of the cerebellar vermis, and that cerebellar vermal abnormalities will be associated with enhanced risk for substance abuse. Three groups of subjects (30 per group) will be identified from the first study. Subjects will either have: (1) had no history of exposure to child abuse trauma; (2) childhood traumatic stress, and PTSD; or (3) childhood traumatic stress and recurrent major depression. Subjects in the three groups will be matched for degree of substance use. Morphometric MRI, T2-relaxometry and proton-echo-planar-spectroscopic imaging will be used to test these hypotheses. These subjects will also receive a probe dose of methylphenidate and a repeat T2-RT scan to test the hypothesis that exposure to childhood traumatic stress enhances hemodynamic response to stimulant drugs in the striatum and cerebellar vermis. Study 3 will test the hypotheses that exposure to childhood traumatic stress produces an increased and more enduring corticotropic, noradrenergic and vasopressin response, (and decreased or delayed oxytocin response) to stress in the Trier Social Stress Test. Overall, these studies will provide new insight into the neurobiological effects of chronic childhood traumatic stress and new understanding of the potential for PTSD and depression to mediate, and MAO-A levels to moderate, the association between early stress and drug abuse. These studies will also pursue the novel hypotheses that stress induced alterations in the cerebellar vermis and in oxytocin release are related to risk for substance abuse in survivors of chronic childhood traumatic stress.