Endocannabinoid system and inhibition in bipolar disorder

描述（由申请人提供）：内源性大麻素（EC）系统是大脑中最重要的调节系统之一，已知影响双相情感障碍（BD）中涉及的神经生物学因素，包括多巴胺（DA），一种与躁狂症和认知障碍相关的神经递质。抑制受损与DA功能障碍相关，是影响日常功能和生活质量的BD的主要特征。DA与其他神经系统之间潜在的相互作用尚不清楚，限制了对双相障碍神经生物学的理解和新治疗方法的发展。由于缺乏全面的翻译范式和对假定反映人类症状的啮齿动物行为的模糊解释，在动物中建立双相障碍神经病理学模型的尝试仍然受到限制。此外，尽管大麻在BD中普遍使用，但EC系统的功能也没有在这种疾病中得到检验。本应用程序将通过跨物种测量，包括一种新的人类开放领域范式（人类行为模式监测或hBPM），研究内源性大麻素在双相障碍患者中的作用及其与去抑制的关系。为了研究EC系统，将比较两种主要内源性大麻素，anandamide （AEA）和2-花生四烯醇甘油酯（2-AG），在生理健康BD受试者和健康志愿者的脑脊液（CSF）水平。我们将通过增加的AEA和2-AG来验证EC系统在BD中长期失调的假设。70名心境平和、非药物滥用的双相障碍受试者（35名服用情绪稳定剂，35名同时服用情绪稳定剂和抗抑郁剂）将与35名没有I轴障碍的受试者进行比较。将检查药物对EC水平的潜在影响。为了研究EC系统与BD中假定的高多巴胺能功能之间的关系，我们将评估脑脊液AEA与脑脊液同质香草酸（HVA）之间的关系，HVA是脑内DA的主要代谢物。第二个目的是验证一个假设，即较低的EC水平（被认为会增加DA传递）与hBPM和其他测量（如5- Choice连续表现任务）中评估的BD去抑制有关。所有提出的认知措施本质上都是跨物种的，允许对双相障碍患者的认知缺陷进行未来的详细检查，并在动物模型中复制。脑脊液HVA与双相障碍受试者运动活动的关系也将被量化，从而确认DA在双相障碍中的作用，并验证基于DA的啮齿动物双相障碍模型。本研究将填补了解内源性大麻素系统和DA在双相障碍中的作用的空白。我们的发现将为未来的研究奠定基础，这些研究将检验大麻在双相障碍中的普遍使用的影响和含义，以及涉及EC系统调节的双相障碍治疗的潜在效用。

DESCRIPTION (provided by applicant): The endocannabinoid (EC) system represents one of the most important modulatory systems in the brain and is known to impact neurobiological factors implicated in Bipolar Disorder (BD), including dopamine (DA), a neurotransmitter associated with mania and cognitive impairments linked to BD. Impaired inhibition is associated with DA dysfunction and is a cardinal feature of BD that affects every day functioning and quality of life. Potential interaction between DA and other neural systems remains unclear, limiting the understanding of the neurobiology of BD and the development of novel treatments. Attempts to model the neuropathology of BD in animals remains limited by a dearth of comprehensive translational paradigms and ambiguity in the interpretation of rodent behaviors postulated to mirror human symptoms. Further, despite prevalent cannabis use in BD, the function of the EC system has also not been examined in this disorder. This application will examine the role of endocannabinoids in people with BD and their relationship to disinhibition using cross- species measures, including a novel human open-field paradigm (the Human Behavior Pattern Monitor or hBPM). To study the EC system, cerebrospinal fluid (CSF) levels of the two primary endogenous cannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), will be compared between euthymic BD subjects and healthy volunteers. We will test the hypothesis that the EC system is chronically dysregulated in BD as indicated by increased AEA and 2-AG. 70 euthymic, non-substance-abusing BD subjects (35 subjects on a mood stabilizer and 35 subjects on a combination of a mood stabilizer and antidepressant) will be compared to 35 subjects without an Axis I disorder. Potential medication effects on EC levels will be examined. In order to examine the relationship between the EC system and putative hyperdopaminergic function in BD, we will assess the association between CSF AEA and CSF homovanillic acid (HVA), the primary DA metabolite in the brain. A secondary aim is to test the hypothesis that lower EC levels, proposed to increase DA transmission, are related to BD disinhibition assessed in the hBPM and other measures such as the 5- Choice Continuous Performance Task. All of the cognitive measures proposed are cross-species in nature, allowing for a future detailed examination of the cognitive deficits seen in BD patients and replicated in animal models. The relationship between CSF HVA and motor activity in BD subjects will also be quantified, enabling confirmation of the role of DA in the disorder and validation of DA-based rodent models of BD. This research will fill a gap in understanding the role of the endocannabinoid system and DA in Bipolar Disorder. Our findings will lay the groundwork for future studies that examine the effects and implications of prevalent cannabis use in BD as well as the potential utility of BD treatments that involve modulation of the EC system. PUBLIC HEALTH RELEVANCE: The endocannabinoid (EC) system is an important brain system which plays a critical role in the regulation of neurotransmitters such as dopamine. Dopamine dysregulation is implicated in the mania and inhibitory deficits associated with Bipolar Disorder (BD), but the relationship between the EC system and dopamine among people with BD has not been well studied. This application will examine the role of the EC system in BD and its association with dopamine as well as the EC system's relationship to disinhibition, and is hoped to lead to better prevention and treatment efforts.