Endocannabinoid modulation of affective signs of cannabinoid withdrawal

内源性大麻素对大麻素戒断情感体征的调节

• 批准号: 8806670
• 负责人: Steven G. Kinsey
• 金额: $ 11.18万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8806670
• 关键词: Abstinence; Adjuvant; Adjuvant Therapy; Affect; Affective; Affective Symptoms; Agitation; Anti-Anxiety Agents; Anxiety; Arousal; Attenuated; Behavior; Behavior Therapy; Behavioral; Behavioral Assay; Biological Assay; Boxing; CNR1 gene; Cannabinoids; Cannabis; Cannabis Abuse; Clinical Treatment; DSM-V; Data; Dependence; Dose; Drug Addiction; Emotional; Endocannabinoids; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Goals; Head; Human; Illicit Drugs; Incidence; Legal; Light; Marble; Marijuana Dependence; Measures; Mental Depression; Metabolism; Modeling; Monoacylglycerol Lipases; Motor Activity; Mus; Opioid; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Plants; Property; Proxy; Publishing; Relapse; Research; Rodent; Role; Substance Withdrawal Syndrome; Symptoms; Testing; Tetrahydrocannabinol; Therapeutic Intervention; Therapeutic Studies; Tissues; Tremor; United States Food and Drug Administration; Withdrawal; Withdrawal Symptom; anandamide; anxiety-like behavior; base; behavior change; cannabinoid dependence; cannabinoid receptor; cannabinoid withdrawal; cannabis withdrawal; craving; dependence relapse; drug of abuse; endogenous cannabinoid system; fatty acid amide hydrolase; in vivo; inhibitor/antagonist; insight; marijuana use disorder; motivated behavior; mouse model; novel strategies; phytocannabinoid; pre-clinical; pre-clinical research; preference; public health relevance; relating to nervous system; research and development; rimonabant; success; synthetic cannabinoid

DESCRIPTION (provided by applicant): Cannabis is universally the most commonly abused illicit drug. Recent legal changes reflect a societal acceptance of cannabis as a "soft drug" with relatively mild withdrawal symptoms, as compared with opioids and other drugs of abuse. However, as recently recognized by the DSM-V, Cannabis Use Disorder and Cannabis Withdrawal Syndrome affect many users, the primary symptoms being increased anxiety, agitation, and cravings for cannabis. Not surprisingly, alleviating the aversive symptoms brought about by abstinence is common cause of relapse. Thus, there is a need to develop new treatments for cannabis dependence. The goal of the proposed studies is to inform clinical treatments for cannabinoid dependence in humans. Current preclinical research on cannabis dependence uses somatic outcomes to quantify cannabis withdrawal. Although these models have been very useful, they do not explore the emotional aspects of cannabis withdrawal that are most salient in humans and contribute directly to relapse. Our preliminary data indicate that withdrawal from �tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, increases preference for the dark portion of the light/dark box and decreases marble burying, a proxy measure of digging. The goal of Aim 1 is to fully characterize these changes in emotionality. We will treat mice repeatedly with THC, and then precipitate withdrawal with the cannabinoid receptor antagonist rimonabant, to elicit and quantify withdrawal behaviors in a battery of tests well known to respond to anti-anxiety drugs. In addition to behavioral interventions, adjuvant therapies have been used with much success to reduce drug dependence. The goal of Aim 2 of the proposed studies is to normalize THC withdrawal-induced behavioral changes by blocking the metabolism of endogenous cannabinoids. The two endocannabinoids are anandamide, which is primarily metabolized in vivo by fatty acid amide hydrolase (FAAH) and 2-arachidonoylethanolamine, which is mainly metabolized by the enzyme monoacylglycerol lipase (MAGL). We propose to selective inhibit FAAH or MAGL in mice undergoing THC withdrawal, and to test alterations in behavioral assays that our unpublished preliminary data indicate are altered by THC withdrawal. It is expected that inhibition of FAAH or MAGL will attenuate THC-withdrawal induced behavioral changes, without any effect on general activity. The successful completion of the proposed project is expected to yield preliminary data for larger scale neural/behavioral project, the goal of which will be to inform cannabinoid dependence research in humans.

描述（由申请人提供）：大麻是全球最常被滥用的非法药物。最近的法律变化反映出，与阿片类药物和其他滥用药物相比，社会接受大麻是一种戒断症状相对轻微的“软毒品”。然而，正如DSM-V最近所认识到的那样，大麻使用障碍和大麻戒断综合症影响到许多使用者，主要症状是焦虑、躁动和对大麻的渴望增加。毫不奇怪，减轻禁欲带来的厌恶症状是复发的常见原因。因此，有必要开发治疗大麻依赖的新方法。拟议研究的目的是为人类大麻素依赖的临床治疗提供信息。目前对大麻依赖的临床前研究使用躯体结果来量化大麻戒断。虽然这些模型非常有用，但它们没有探索大麻戒断的情感方面，这在人类中最为突出，并直接导致复发。我们的初步数据表明，从大麻的主要精神活性成分——四氢大麻酚（THC）中提取大麻，会增加人们对光明/黑暗盒子黑暗部分的偏好，并减少大理石掩埋，这是挖掘的替代措施。Aim 1的目标是充分描述情绪的这些变化。我们将用四氢大麻酚反复治疗小鼠，然后用大麻素受体拮抗剂利莫那班沉淀戒断，在一系列众所周知的抗焦虑药物反应测试中引发和量化戒断行为。除了行为干预外，辅助疗法已被成功地用于减少药物依赖。拟议研究的目标2是通过阻断内源性大麻素的代谢使四氢大麻酚戒断引起的行为改变正常化。这两种内源性大麻素分别是anandamide和2-花生四烯酰基乙醇胺，前者在体内主要由脂肪酸酰胺水解酶（FAAH）代谢，后者主要由单酰基甘油脂肪酶（MAGL）代谢。我们建议选择性抑制四氢大麻酚戒断小鼠的FAAH或MAGL，并测试未发表的初步数据表明四氢大麻酚戒断会改变行为分析的变化。预计抑制FAAH或MAGL将减弱thc戒断引起的行为改变，而不会对一般活性产生任何影响。该项目的成功完成有望为更大规模的神经/行为项目提供初步数据，其目标将是为人类大麻素依赖研究提供信息。