Early Stress and Neural Substrates Relevant To Addiction

早期压力和与成瘾相关的神经基质

• 批准号: 6803612
• 负责人: MARTIN H TEICHER
• 金额: $ 30.93万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803612
• 关键词: adrenocorticotropic hormone; behavioral /social science research tag; brain circulation; brain morphology; central nervous system stimulants; child abuse; clinical research; cortisol; developmental neurobiology; developmental psychology; disease /disorder proneness /risk; dopamine; drug addiction; electroencephalography; heart rate; hemodynamics; human subject; magnetic resonance imaging; negative reinforcements; neuropharmacology; neuropsychological tests; oxytocin; sex abuse; stress; stressor; vasopressins

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.

描述（由申请人提供）： 童年时期的慢性反复压力已被认为是晚年药物滥用和成瘾行为的危险因素。目前，人们对这种情况发生的机制知之甚少。这些研究旨在检验这样的假设：儿童时期暴露于慢性重复压力源会产生一系列分子和细胞事件，对大脑结构和功能发育产生持久影响，而这些变化导致更容易吸毒、成瘾或复发。具体而言，将有遭受过严酷压力体罚史的 18-22 岁受试者 (n = 50) 与没有早期压力史的健康对照组 (n = 50) 进行比较，MRI 测量将检查压力暴露对胼胝体、杏仁核和小脑蚓部形态测量的影响。将使用磁共振波谱法评估新皮质和胼胝体中的神经元密度/活力。还将使用弥散张量成像对胼胝体进行评估，以提供有关穿过该区域的神经纤维的方向和质量的信息。 T2 松弛测量法将用于评估左右半球的血流量差异以及小脑蚓部的功能活动程度。受试者将接受哌醋甲酯的探针剂量挑战，以测试以下假设：暴露于慢性早期应激会通过使多巴胺系统对精神兴奋剂的血流动力学反应敏感而增加药物滥用的风险。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在青少年晚期 - 早期成人时是否表现出增强的压力反应。压力反应将通过压力源期间和之后皮质醇、促肾上腺皮质激素、加压素、催产素和心率的波动来评估。具有重复性早期应激史的受试者预计皮质醇和促肾上腺皮质激素对应激的反应会增加，催产素反应会减弱，并且需要更长的恢复期才能恢复到基线。总的来说，这些研究将为早期压力对可能介导药物滥用倾向的神经基质的可能影响提供新的见解。