Cannabis use and the endocannabinoid system in bipolar disorder

摘要（家长资助）：大麻是使用的所有双相情感障碍（BD），这可能 随着美国各地的持续合法化而增加。一些但不是所有的有害认知 大麻的影响可能在BD患者中被夸大，因为大脑中的内源性大麻素（ECB） 系统影响多巴胺能（DA）回路的功能，其被认为在BD中失调。为 例如，给予大麻素1（CB1）受体激动剂δ-9-四氢大麻二酚（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 在多巴胺转运蛋白（DAT）表达减少的BD个体中， DA水平的稳态调节。另一方面，大麻二酚（CBD）是大麻的另一种主要成分。 大麻不会增加DA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 神经化学在BD中的应用可以进一步发展BD和物质使用障碍的治疗。的 建议使用跨物种的措施和人类和啮齿动物的平行研究， 对BD中ECB系统的神经生物学和临床适用性的细致入微的理解。目标1将 确定慢性大麻使用者中慢性大麻使用对BD相关认知功能的影响 和非使用者与健康对照（HC）参与者进行比较。一系列认知和行为测试 这些领域包括唤醒、抑制控制、基于反馈的决策、奖励偏好 并将管理时间感知。目标2将确定急性暴露于受控的 剂量的THC和CBD对认知的影响，并确定内源性大麻素的水平， 花生四烯酸（AEA）和DA代谢产物高香草酸（HVA）。偶尔抽大麻- 使用BD和HC的参与者将随机接受安慰剂、THC或THC/CBD的3种制剂之一 并将接受认知行为测试目标3将确定减少的 DAT功能（经验证的BD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 对上述人体试验具有直接的转化应用性。假设BD参与者 DAT表达减少的小鼠将显示出长期使用大麻的交互和累加效应， 在认知和ECB和HVA水平，由于ECB和DA系统之间的复杂的相互作用。急性 THC暴露可降低BD和KD小鼠的觉醒并改善时间知觉，但损害抑制 和决策，而CBD不会产生有害影响。除了提供新的线索外， BD和大麻使用障碍的神经生物学，这些研究可能会告知如何药理学操作 ECB系统可以成为治疗BD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.