Inhibitory Deficits in Bipolar Disorder and Methamphetamine Dependence

描述(由申请人提供)：抑制，即抑制或减弱一种行为或一种思想的能力，在行为调节中具有核心重要性。抑制缺陷是双相情感障碍(BD)和药物滥用障碍的主要特征，包括对甲基苯丙胺(MA)的依赖。BD是全球导致残疾的主要原因之一，仅在美国，每年损失的工作日估计为9600万天，工资损失140亿美元。虽然有报告指出大部分屋宇署署长均同时滥用药物，并与较严重的精神症状和较差的治疗结果有关，但大部分涉及屋宇署的研究和临床试验都把有滥用药物史的受试者排除在外。本项目的目标是使用我们实验室开发的一种新的人类开放领域范式来检验MA依赖和BD对抑制缺陷的影响。对并发MA依赖的BD患者的抑制失败的评估将有助于开发一种模型，该模型可用于预测这些疾病的新治疗方法，并有助于识别这些疾病背后的神经底物。抑制缺陷表现为多动增加、持之以恒的行为，以及以冲动为特征的症状，包括对新奇事物的反应增加。这个项目的第一个目标是评估MA和BD对被放置在一个新房间中的个体的这些行为的影响，在这个房间里，运动活动、持久性运动反应以及与新物体的互动被量化。根据基底节多巴胺能系统的激活/敏化和前额叶皮质的损伤(大脑中调节行为抑制的区域)的证据，我们预测有MA依赖的慢性病史的BD患者将观察到最严重的抑制缺陷。我们项目的第二个目标将检查躁狂症的临床评估和人类开放领域范例中抑制缺陷之间的关系。我们预测，用青年躁狂评定量表衡量，躁狂症状的增加将与抑制缺陷的增加显示出显著的相关性。公共卫生相关性：我们对BD的理解和治疗以及并发药物依赖的影响将极大地受益于该人群中发生的行为障碍的人类模型的发展。这个项目将提高我们对BD的病因学和病理学的理解，并使用一种有助于诊断和测试情绪和药物滥用障碍的治疗方法的范例。

DESCRIPTION (provided by applicant): Inhibition, i.e. the ability to withhold or attenuate an action or a thought, is of central importance in the regulation of behavior. Inhibitory deficits are key features of Bipolar Disorder (BD) and substance abuse disorders, including methamphetamine (MA) dependence. BD is one of the leading causes of disability worldwide, with an estimated cost of 96 million lost workdays and 14 billion dollars in salary per year in the United States alone. Although comorbid drug abuse has been reported to occur in a majority of BD individuals and is associated with more severe psychiatric symptoms and worse treatment outcome, most research studies and clinical trials involving BD have excluded subjects with a history of drug abuse. The objective of the current project is to examine the effect of both MA dependence and BD on deficits in inhibition using a novel human open field paradigm that we have developed in our lab. The assessment of inhibitory failure in BD individuals with concurrent MA dependence will enable the development of a model that may be used to predict novel treatments for these pathologies and help to identify the neural substrates underlying these disorders. Inhibitory deficits manifest as increased hyperactivity, perseverative behavior, and symptoms characterized by impulsivity, including increased responses to novelty. The first aim of this project will assess the effect of MA and BD on these behaviors in individuals placed into a novel room where locomotor activity, perseverative motor responses, and interactions with novel objects are quantified. Based on evidence for activation/sensitization of the dopaminergic system in the basal ganglia and damage to the prefrontal cortex, a region of the brain that mediates inhibition of behavior, we predict the most severe inhibitory deficits will be observed in BD individuals with a chronic history of MA dependence. The second aim of our project will examine the relationship between the clinical assessment of mania and deficits in inhibition in our human open field paradigm. We predict that increased manic symptoms, as measured by the Young Mania Rating Scale, will show a significant correlation with increased inhibitory deficits. PUBLIC HEALTH RELEVANCE: Our understanding and treatment of BD and the effects of concurrent drug dependence will greatly benefit from the development of a human model of the behavior dysfunction that occurs in this population. This project will improve our understanding of the etiology and pathology of BD and uses a paradigm that can help to diagnose and test treatments for the mood and substance abuse disorders.