Endocannabinoid system and inhibition in bipolar disorder

描述(申请人提供)：内源性大麻素(EC)系统代表大脑中最重要的调节系统之一，已知影响与双相情感障碍(BD)有关的神经生物学因素，包括多巴胺(DA)，一种与躁狂症和与BD相关的认知障碍相关的神经递质。抑制功能受损与DA功能障碍有关，是BD的一个基本特征，影响日常功能和生活质量。DA和其他神经系统之间的潜在相互作用尚不清楚，限制了对BD神经生物学的了解和新治疗方法的开发。在动物身上模拟BD的神经病理学的尝试仍然受到缺乏全面的翻译范例和对啮齿动物行为解释的模棱两可的限制，这些行为被认为是反映人类症状的。此外，尽管在BD中普遍使用大麻，但EC系统的功能在这种疾病中也没有得到检查。这项应用将研究内源性大麻素在BD患者中的作用，以及它们与使用跨物种措施解除抑制的关系，包括一种新的人类开放领域范例(人类行为模式监测器或HBPM)。为了研究EC系统，我们将比较两种主要的内源性大麻素--烷胺(AEA)和2-花生四烯基甘油(2-AG)在良性BD患者和健康志愿者脑脊液(CSF)中的水平。我们将检验假设，即EC系统在BD中长期失调，如AEA和2-AG升高所示。70名情绪愉悦、不滥用物质的BD受试者(35名服用情绪稳定剂的受试者和35名服用情绪稳定剂和抗抑郁药的受试者)将与35名没有轴心I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可能的高多巴胺能功能之间的关系，我们将评估脑脊液AEA和脑内主要DA代谢物脑脊液高香草酸(HVA)之间的关系。第二个目的是检验这一假设，即较低的EC水平，被提议增加DA传递，与HBPM和其他衡量标准(如5-Choice持续绩效任务)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，允许未来对BD患者的认知缺陷进行详细检查，并在动物模型中复制。BD受试者的脑脊液HVA和运动活动之间的关系也将被量化，从而能够确认DA在BD啮齿动物模型的紊乱和验证中的作用。这项研究将填补了解内源性大麻素系统和多巴胺在双相情感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，这些研究将检查BD中流行的大麻使用的影响和影响，以及BD治疗的潜在效用，涉及EC系统的调节。

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.