Endocannabinoid system and inhibition in bipolar disorder

描述（由申请人提供）：内源性大麻素（EC）系统代表大脑中最重要的调节系统之一，已知会影响双相情感障碍（BD）中涉及的神经生物学因素，包括多巴胺（DA），一种与躁狂和BD相关的认知障碍相关的神经递质。抑制受损与DA功能障碍相关，是BD的主要特征，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仍不清楚，限制了对BD神经生物学的理解和新治疗方法的开发。在动物中模拟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的解释的模糊性的限制，这些行为被假设为反映人类症状。此外，尽管流行大麻使用BD，EC系统的功能也没有在这种疾病中进行检查。本申请将使用跨物种测量，包括一种新的人类开放领域范式（人类行为模式监测器或hBPM），研究内源性大麻素在BD患者中的作用及其与去抑制的关系。为了研究EC系统，将在正常胸腺BD受试者和健康志愿者之间比较两种主要内源性大麻素花生四烯酸（AEA）和2-花生四烯酸甘油（2-AG）的脑脊液（CSF）水平。我们将检验这一假设，即EC系统是慢性失调，在BD所示的增加AEA和2-AG。将70名情绪正常、非物质滥用BD受试者（35名受试者接受情绪稳定剂治疗，35名受试者接受情绪稳定剂和抗抑郁剂的组合治疗）与35名无轴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系统和假定的高多巴胺能功能之间的关系，在BD，我们将评估CSF AEA和CSF高香草酸（HVA），在大脑中的主要DA代谢产物之间的关联。第二个目的是检验假设，即较低的EC水平，建议增加DA传输，与BD去抑制评估的hBPM和其他措施，如5选择连续性能任务。所有提出的认知措施都是跨物种的性质，允许未来详细检查BD患者的认知缺陷，并在动物模型中复制。还将量化BD受试者中CSF HVA与运动活动之间的关系，从而能够确认DA在疾病中的作用并验证基于DA的BD啮齿动物模型。这项研究将填补了解内源性大麻素系统和DA在双相情感障碍中的作用的空白。我们的研究结果将为未来的研究奠定基础，这些研究将检查BD中普遍使用大麻的影响和影响，以及涉及EC系统调节的BD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.