Early Stress and Neural Substrates Relevant To Addiction

描述（由申请人提供）： 儿童时期的慢性反复压力已被认为是以后生活中药物滥用和成瘾行为的危险因素。目前，人们对这种情况可能发生的机制知之甚少。这些研究旨在检验以下假设：儿童时期长期反复受到压力，会产生一连串的分子和细胞事件，对大脑结构和功能发育产生持久影响，这些变化是导致更容易使用药物、成瘾或复发的原因。具体地，将具有暴露于严酷的压力性体罚的历史的18-22岁受试者（n = 50）与没有早期压力历史的健康对照（n = 50）进行比较。MRI测量将检查压力暴露对胼胝体、杏仁核和小脑蚓部的形态测量的影响。将使用磁共振波谱评估新皮质和胼胝体中的神经元密度/活力。还将使用扩散张量成像评估胼胝体，以提供关于穿过该区域的神经纤维的方向和质量的信息。将使用T2松弛测量法评估左右半球血流差异和小脑蚓部功能活动程度。受试者将接受哌醋甲酯的探针剂量挑战，以检验暴露于慢性早期应激通过致敏多巴胺系统对精神刺激物的血流动力学反应增加药物滥用风险的假设。受试者还将接受社会压力测试，以确定具有早期重复压力史的受试者是否在青少年晚期-成年早期表现出增强的压力反应。将通过应激刺激期间和之后皮质醇、ACTH、加压素、催产素和心率的波动来评估应激反应。具有暴露于重复性早期压力的历史的受试者被预测具有增加的皮质醇和ACTH对压力的反应，减少的催产素反应，并且需要更长的恢复期才能恢复到基线。总的来说，这些研究将提供新的见解，早期压力对神经基质可能介导的药物滥用的责任。

DESCRIPTION (provided by applicant): Chronic repeated stress during childhood has been recognized to be a risk factor for substance abuse and addictive behaviors later in life. At the present time there is little understanding of mechanisms through which this may occur. These studies are designed to test the hypothesis that exposure to chronic repeated stressors during childhood produces a cascade of molecular and cellular events that exert enduring effects on structural and functional brain development, and that these changes are responsible for the enhanced vulnerability to substance use, addiction or relapse. Specifically, 18-22 year old subjects with a history of exposure to harsh stressful corporal punishment (n = 50) will be compared to healthy controls with no history of early stress (n = 50) MRI measures will examine the effects of stress exposure on the morphometry of the corpus callosum, amygdala and cerebellar vermis. Neuronal density/viability in the neocortex and corpus callosum will be assessed using magnetic resonance spectroscopy. The corpus callosum will also be assessed using diffusion tensor imaging to provide information on the orientation and quality of nerve fibers passing through the region. T2-relaxometry will be used to assess left-right hemisphere differences in blood flow, and extent of functional activity in the cerebellar vermis. Subjects will receive probe dose challenge of methylphenidate to test the hypothesis that exposure to chronic early stress enhances risk for substance abuse by sensitized dopamine system hemodynamic response to psychostimutants. Subjects will also be exposed to a social stress test to ascertain whether subjects with a history of early repeated stress show enhanced stress responses as late adolescents - early adults. Stress response will be assessed by fluctuations in cortisol, ACTH, vasopressin, oxytocin and heart rate during and following the stressor. Subjects with a history of exposure to repetitive early stress are predicted to have an increased cortisol and ACTH responses to stress, a diminished oxytocin response, and to require a longer recovery period to return to baseline. Overall, these studies will provide new insight into the possible effects of early stress on neural substrates that may mediate substance abuse liability.