Inhibitory Deficits in Bipolar Disorder and Methamphetamine Dependence

描述（由申请人提供）：抑制，即抑制或减弱一个动作或想法的能力，在行为调节中是至关重要的。抑制性缺陷是双相情感障碍（BD）和物质滥用障碍（包括甲基苯丙胺（MA）依赖）的关键特征。双相障碍是世界范围内导致残疾的主要原因之一，仅在美国，每年就造成9600万个工作日的损失和140亿美元的工资损失。虽然据报道，大多数双相障碍患者存在共病性药物滥用，并伴有更严重的精神症状和更差的治疗结果，但大多数涉及双相障碍的研究和临床试验都排除了有药物滥用史的受试者。当前项目的目标是使用我们在实验室开发的一种新的人类开放领域范式来检查MA依赖和BD对抑制缺陷的影响。对双相障碍患者同时存在MA依赖的抑制性衰竭的评估将有助于建立一个模型，该模型可用于预测这些病理的新治疗方法，并有助于识别这些疾病背后的神经基质。抑制性缺陷表现为多动、持续行为和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对个体这些行为的影响，这些个体被放置在一个新的房间里，在这个房间里，运动活动、持续性运动反应和与新物体的相互作用被量化。基于基底节区多巴胺能系统的激活/敏化和前额叶皮层（大脑中调节行为抑制的区域）的损伤的证据，我们预测在有慢性MA依赖史的双相障碍患者中会观察到最严重的抑制性缺陷。我们项目的第二个目标将在我们的人类开放领域范例中检查躁狂症的临床评估和抑制缺陷之间的关系。我们预测，增加的躁狂症状，如测量的青年躁狂评定量表，将显示出显著的相关性增加的抑制缺陷。公共卫生相关性：我们对双相障碍的理解和治疗以及并发药物依赖的影响将极大地受益于在这一人群中发生的行为功能障碍的人类模型的发展。该项目将提高我们对双相障碍的病因和病理的理解，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.