Cannabis use and the endocannabinoid system in bipolar disorder

摘要(家长资助)：超过一半的双相情感障碍患者使用大麻，这可能是一种 随着美国各地合法化的继续，这一数字也在增加。一些但不是全部有害的认知 考虑到大脑的内源性大麻素(ECB)，大麻对BD患者的影响可能被夸大了。 系统影响多巴胺能(DA)回路的功能，这被认为是BD的失调。为 例如，注射大麻素受体激动剂Delta-9-四氢大麻二醇(THC)-- 大麻中的主要活性成分--增加纹状体中DA的释放。这种影响尤其成问题。 在多巴胺转运体(DAT)表达减少的BD患者中，驱动机制 多巴胺水平的动态平衡调节。另一方面，大麻二酚(CBD)是另一种主要成分 大麻不会增加多巴胺的水平，因此含有高CBD的大麻可能没有那么有害。更好的 了解长期使用大麻对关键认知功能和ECB/DA的影响 BD的神经化学可以进一步发展BD和物质使用障碍的治疗方法。这个 拟议在人类和啮齿动物中使用跨物种措施和平行研究能够使 对欧洲央行系统在BD中的神经生物学和临床适用性的细微差别的理解。目标1将 确定长期使用大麻对慢性大麻使用者与BD相关的认知功能的影响 与健康对照(HC)参与者进行比较。一系列认知和行为测试 测量领域，如唤醒，抑制控制，基于反馈的决策，奖励偏好， 时间知觉将被用来管理。目标2将确定急性接触受控辐射的影响 THC和CBD的剂量对认知的影响并确定由此产生的内源性大麻素的水平，如 安非他明(AEA)和DA代谢物高香草酸(HVA)经腰穿。罕见的大麻- 使用BD和HC的参与者将随机接受安慰剂、THC或THC/CBD三种制剂中的一种 并将在认知行为电池上进行测试。目标3将确定减少的交互影响 DAT功能(BD的有效小鼠模型)和THC/CBD治疗(急性、慢性和戒断状态) 对小鼠认知、神经病理学以及ECB、DA受体和AEA表达的影响。啮齿动物行为测试 对上述人体测试具有直接的翻译适用性。假设BD参与者 DAT表达降低的小鼠将表现出长期使用大麻的交互和相加效应 在认知以及欧洲央行和HVA水平上，由于欧洲央行和DA系统之间的复杂相互作用。急性 暴露THC可降低BD和KD小鼠的觉醒和改善时间知觉，但会削弱抑制 和决策，而CBD不会发挥有害的影响。除了让我们了解更多关于 神经生物学的BD和大麻使用障碍，这些研究可能会告诉我们如何进行药物操作 欧洲央行系统可以成为治疗BD的一种新方法。

Abstract (Parent grant): Cannabis is used by more than half of all people with bipolar disorder (BD), which may increase with continued legalization across the United States. Some but not all of the deleterious cognitive effects of cannabis are likely exaggerated in people with BD, given that the brain's endocannabinoid (ECB) system affects the function of dopaminergic (DA) circuitry, which is thought to be dysregulated in BD. For example, administration of the cannabinoid1 (CB1) receptor agonist delta-9-tetrahydrocannabidiol (THC) - the primary active ingredient in cannabis - increases DA release in the striatum. This effect is especially problematic in BD individuals who have reduced expression of the dopamine transporter (DAT), the mechanism driving homeostatic regulation of DA levels. On the other hand, cannabidiol (CBD) is the other major ingredient of cannabis and does not increase DA levels, so cannabis containing high CBD may not be as deleterious. A better understanding of the consequences of chronic cannabis use on critical cognitive functions and ECB/DA neurochemistry in BD could further the development of treatments for BD and substance use disorders. The proposed use of cross-species measures and parallel studies in both humans and rodents enables a more nuanced understanding of both the neurobiology and clinical applicability of the ECB system in BD. Aim 1 will determine the effects of chronic cannabis use on cognitive functions relevant to BD, in chronic cannabis users and non-users compared to healthy comparison (HC) participants. A battery of cognitive and behavioral tests that measure domains such as arousal, inhibitory control, feedback-based decision making, reward preference, and temporal perception will be administered. Aim 2 will identify the effects of acute exposure to controlled doses of THC and CBD on cognition and determine the resulting levels of endogenous cannabinoids such as anandamide (AEA) and the DA metabolite homovanillic acid (HVA) via lumbar puncture. Infrequent cannabis- using BD and HC participants will be randomized to receive one of 3 preparations of placebo, THC, or THC/CBD and will be tested on the cognitive-behavioral battery. Aim 3 will determine the interactive effects of reduced DAT function (a validated mouse model for BD) and THC/CBD treatment (acute, chronic, and withdrawal states) on cognition, neuropathology, plus ECB, DA receptor, and AEA expression in mice. The rodent behavioral tests have direct translational applicability to the human tests described above. It is hypothesized that BD participants and mice with reduced DAT expression will show interactive and additive effects of chronic cannabis use both on cognition and on ECB and HVA levels, due to complex interactions between the ECB and DA systems. Acute THC exposure may decrease arousal and improve temporal perception in BD and KD mice but impair inhibition and decision making, whereas CBD will not exert as deleterious effects. In addition to shedding new light on the neurobiology of BD and cannabis use disorder, these studies may inform how pharmacological manipulation of the ECB system can become a novel approach for treating BD.