Cannabis use and the endocannabinoid system in bipolar disorder

双相情感障碍中的大麻使用和内源性大麻素系统

• 批准号: 10357764
• 负责人: WILLIAM PERRY
• 金额: $ 57.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357764
• 关键词: Abstinence; Acute; Affect; Age; Age of Onset; Agonist; Alzheimer' s Disease; Animal Experimentation; Arousal; Attenuated; Automobile Driving; Behavior; Behavioral; Biological; Bipolar Disorder; Bipolar I; Brain; Brain region; Cancer Burden; Cannabidiol; Cannabis; Chronic; Cognition; Cognitive; Cognitive deficits; Complex; Corpus striatum structure; Decision Making; Dopamine; Dose; Economic Burden; Endocannabinoids; Exposure to; Feedback; Functional disorder; Goals; Health Care Costs; Hippocampus (Brain); Homovanillic Acid; Human; Hyperactivity; Impairment; Individual; Knowledge; Lead; Legal; Light; Limbic System; Manic; Measures; Mediation; Mental disorders; Mus; Neurobiology; Neurocognitive; Neurotransmitters; Outcome; Participant; Patients; Perception; Persons; Pharmacology; Placebos; Play; Population; Prefrontal Cortex; Preparation; Psychiatry; Race; Randomized; Regulation; Reporting; Rewards; Risk; Rodent; Rodent Model; Role; Severity of illness; Spinal Puncture; Substance Use Disorder; Substance abuse problem; Symptoms; System; Testing; Tetrahydrocannabinol; Thinking; Time; United States; Wild Type Mouse; Withdrawal; addiction; anandamide; base; behavior test; cannabinoid receptor; clinical application; cognitive control; cognitive function; cognitive testing; comorbidity; dopamine transporter; endogenous cannabinoid system; functional outcomes; improved; marijuana use; marijuana use disorder; marijuana user; mouse model; neurochemistry; neuropathology; novel; novel strategies; preference; prepulse inhibition; receptor; receptor expression; recruit; reduce symptoms; therapy development

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.

大麻是使用超过一半的所有人与双相情感障碍（BD），这可能会增加与持续 在美国各地合法化。大麻的一些但不是所有的有害认知影响都是 这可能在BD患者中被夸大了，因为大脑的内源性大麻素（ECB）系统会影响BD的功能。 多巴胺（DA）电路，这被认为是失调的BD。例如， 大麻素1（CB 1）受体激动剂δ-9-四氢大麻二酚（THC）-大麻素1（CB 1）受体激动剂的主要活性成分， 大麻-增加纹状体中DA的释放。这种影响在BD个体中尤其成问题， 多巴胺转运蛋白（DAT）的表达减少，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， 增加DA水平，因此含有高CBD的大麻可能不那么有害。更好地理解 慢性大麻使用对BD患者关键认知功能和ECB/DA神经化学的影响可能 进一步发展BD和物质使用障碍的治疗。建议使用跨- 在人类和啮齿动物中进行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将决定 慢性大麻使用者和非使用者中慢性大麻使用对BD相关认知功能的影响 与健康对照（HC）参与者相比。一系列认知和行为测试， 领域，如唤醒，抑制控制，基于反馈的决策，奖励偏好，和时间 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的水平，如大麻素 (AEA)和DA代谢产物高香草酸（HVA）。不经常使用大麻-BD和 HC参与者将随机接受安慰剂、THC或THC/CBD 3种制剂之一，并将 进行认知行为测试目标3将确定减少DAT功能的交互作用 （BD的经验证的小鼠模型）和THC/CBD治疗（急性，慢性和戒断状态）对 小鼠的认知、神经病理学，加上ECB、DA受体和AEA表达。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 DAT表达减少的参与者和小鼠将显示出慢性免疫的交互和累加效应。 大麻使用对认知和ECB和HVA水平，由于ECB之间的复杂相互作用， 和DA系统。急性THC暴露可降低BD和KD的觉醒并改善时间感知 小鼠，但损害抑制和决策，而CBD不会发挥有害作用。此外 为了对BD和大麻使用障碍的神经生物学提供新的认识，这些研究可能会告知如何 ECB系统的药理学操作可以成为治疗BD的新方法。