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，这种情况可能会随着时间的推移而增加 整个美国的合法化。大麻的一些但不是全部有害的认知影响是 在BD患者中可能被夸大了，因为大脑的内源性大麻素(ECB)系统会影响功能 多巴胺能(DA)回路，被认为在BD中调节失调。例如，管理 大麻素(CB1)受体激动剂Delta-9-四氢大麻二醇(THC)- 大麻--增加纹状体中DA的释放。这种影响在患有BD的人中尤其成问题 减少多巴胺转运体(DAT)的表达，DAT是驱动体内平衡调节的机制 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 提高多巴胺水平，因此含有高CBD的大麻可能没有那么有害。更好地理解 慢性大麻使用对BD患者关键认知功能和ECB/DA神经化学的影响 进一步开发BD和药物使用障碍的治疗方法。建议使用的交叉式- 在人类和啮齿动物中的物种测量和平行研究使我们能够更细微地理解 ECB系统在BD中的神经生物学和临床适用性。目标1将确定 慢性大麻吸毒者和非吸毒者对与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 领域，如唤醒、抑制控制、基于反馈的决策、奖励偏好和时间 知觉将被施以。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，并确定由此产生的内源性大麻素的水平，如花椒胺 (AEA)和DA代谢物高香草酸(HVA)。不常吸食大麻--使用BD和 HC参与者将随机接受安慰剂、THC或THC/CBD 3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DAT功能的交互影响 (BD的有效小鼠模型)和THC/CBD治疗(急性、慢性和戒断状态) 认知，神经病理学，以及ECB，DA受体和AEA在小鼠中的表达。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。据推测，BD 参与者和DAT表达降低的小鼠将显示出慢性 由于欧洲央行之间复杂的相互作用，大麻在认知以及欧洲央行和HVA水平上都有使用 和地区检察官系统。急性THC暴露可降低BD和KD患者的觉醒并改善其时间知觉 但会损害小鼠的抑制和决策能力，而CBD不会产生有害的影响。此外 为了对BD和大麻使用障碍的神经生物学有新的了解，这些研究可能会告诉我们 对欧洲央行系统的药理学操作可以成为治疗BD的一种新方法。

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.