Cannabis use and the endocannabinoid system in bipolar disorder

超过一半的双相情感障碍 (BD) 患者使用大麻，这一数字可能会随着持续的增加而增加 美国各地的合法化。大麻的一些但不是全部有害的认知影响是 鉴于大脑的内源性大麻素 (ECB) 系统会影响功能，因此 BD 患者的这种情况可能会被夸大 多巴胺能 (DA) 回路被认为在 BD 中失调。例如，管理 大麻素 1 (CB1) 受体激动剂 delta-9-四氢大麻二酚 (THC) - 主要活性成分 大麻 - 增加纹状体中 DA 的释放。这种效应对于 BD 个体来说尤其成问题 多巴胺转运蛋白（DAT）的表达减少，多巴胺转运蛋白是驱动体内稳态调节的机制 DA 水平。另一方面，大麻二酚（CBD）是大麻的另一种主要成分，并不 增加 DA 水平，因此含有高 CBD 的大麻可能不会那么有害。更好地理解 长期使用大麻对 BD 中关键认知功能和 ECB/DA 神经化学的影响可能 进一步开发 BD 和物质使用障碍的治疗方法。建议使用交叉 对人类和啮齿动物的物种测量和平行研究使人们能够更细致地了解 ECB 系统在 BD 中的神经生物学和临床适用性。目标 1 将确定以下效果： 长期使用大麻对慢性大麻使用者和非使用者中与 BD 相关的认知功能的影响 与健康对照（HC）参与者相比。一系列认知和行为测试 唤醒、抑制控制、基于反馈的决策、奖励偏好和时间等领域 感知将被管理。目标 2 将确定急性暴露于受控剂量的 THC 的影响 和 CBD 对认知的影响，并确定内源性大麻素（如 anandamide）的水平 (AEA) 和 DA 代谢物高香草酸 (HVA) 通过腰椎穿刺。不经常使用大麻 BD 和 HC 参与者将被随机接受 3 种安慰剂、THC 或 THC/CBD 制剂中的一种，并将 在认知行为电池上进行了测试。目标 3 将确定减少 DAT 功能的交互效果 （经过验证的 BD 小鼠模型）和 THC/CBD 治疗（急性、慢性和戒断状态） 小鼠的认知、神经病理学以及 ECB、DA 受体和 AEA 表达。啮齿动物行为测试 对上述人体测试具有直接的转化适用性。假设BD DAT 表达减少的参与者和小鼠将表现出慢性 由于欧洲央行之间复杂的相互作用，大麻的使用既影响认知，又影响欧洲央行和 HVA 水平 和DA系统。急性 THC 暴露可能会降低 BD 和 KD 的觉醒并改善时间知觉 但会损害小鼠的抑制和决策能力，而 CBD 不会产生有害影响。另外 为了对 BD 和大麻使用障碍的神经生物学提供新的认识，这些研究可能会告诉我们如何 ECB 系统的药理学操作可以成为治疗 BD 的新方法。

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.