Early Stress, PTSD, and the Neurobiology of Addiction

儿童时期反复遭受压力和创伤会产生一连串的分子和细胞事件，这些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脆弱性增加。研究1将检验PTSD和复发性重性抑郁症介导儿童创伤性应激与药物滥用风险增加之间关联的假设。这项研究还将测试 假设MAO-A启动子的功能多态性产生低水平的MAO-A活性，这将与儿童创伤应激对药物使用的不利影响的脆弱性增加有关。这些假设将在一个20-25奥尔兹的样本中进行测试（n=500），这些样本要么没有儿童期虐待的暴露史，要么有满足PTSD A（1）A（2）标准的儿童期虐待暴露史。研究2将测试暴露于慢性儿童创伤应激影响小脑蚓部的形态，神经元的完整性和顺磁特性，以及小脑蚓部异常将与药物滥用的风险增加的假设。将从第一项研究中确定三组受试者（每组30例）。受试者将有：（1）没有儿童虐待创伤史;（2）儿童创伤性应激和PTSD;或（3）儿童创伤性应激和复发性重度抑郁症。三组受试者的物质使用程度将匹配。将使用形态测量MRI、T2弛豫测量和质子回波平面光谱成像来检验这些假设。这些受试者还将接受哌醋甲酯的探测剂量和重复T2-RT扫描，以测试以下假设：暴露于儿童创伤应激增强纹状体和小脑蚓部对兴奋剂药物的血流动力学反应。研究3将检验以下假设：在特里尔社会压力测试中，暴露于儿童创伤性压力会增加和更持久地产生促皮质激素、去甲肾上腺素能和加压素反应（以及减少或延迟的催产素反应）。总的来说，这些研究将提供新的见解， 慢性儿童创伤性应激的神经生物学效应，以及对PTSD和抑郁症的潜在介导作用的新认识，以及MAO-A水平的适度，早期应激与药物滥用之间的关联。这些研究还将追求新的假设，即压力引起的小脑蚓部和催产素释放的变化与慢性儿童创伤压力幸存者滥用药物的风险有关。

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.