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（由适用提供）：大麻普遍是最常见的滥用非法药物。最近的法律变化反映了与阿片类药物和其他滥用药物相比，大麻作为一种“软药物”具有相对轻度戒断症状的“软药物”。但是，正如DSM-V最近认可的那样，大麻使用障碍和大麻戒断综合症会影响许多用户，主要症状是增加焦虑，躁动和大麻的渴望。毫不奇怪，减轻禁欲带来的厌恶症状是退休的普遍原因。这是有必要开发大麻依赖的新疗法。拟议研究的目的是为人类的大麻素依赖性提供临床治疗。当前对大麻依赖性的临床前研究使用躯体结局来量化大麻戒断。尽管这些模型非常有用，但它们并没有探索大麻戒断的情感方面，这些方面在人类中最为突出，直接有助于缓解。我们的初步数据表明，大麻的主要精神活性成分从四氢大麻酚（THC）提取，它增加了对光/深色盒的黑暗部分的偏爱，并减少了大理石埋葬，这是一种代理挖掘的措施。目标1的目的是充分表征情感上的这些变化。我们将用THC反复治疗小鼠，然后用大麻素接收器拮抗剂rimonabant进行宝贵的戒断，以在一系列众所周知的测试中引起和量化戒断行为，以应对抗焦虑药。除了行为干预外，调整疗法已被成功地使用以减少药物依赖性。拟议研究的目标2的目的是通过阻止内源性大麻素的代谢来使THC戒断诱导的行为变化归一化。两种内源性大麻素是anandamide，主要由脂肪酸酰胺水解酶（FAAH）和2-芳基二烯酰甲醇胺在体内代谢，主要由酶单酰基甘油糖脂肪酶（MAGL）代谢。我们建议选择性抑制FAAH或MAGL的小鼠进行THC戒断，并测试行为分析的改变，即我们未发表的初步数据通过THC撤回来改变。可以预期，抑制法族或MAGL会衰减Thc-WithDrawal诱导的行为变化，而不会对一般活动产生任何影响。预计拟议项目的成功完成将为大规模的神经/行为项目产生初步数据，其目的是告知人类中的大麻素依赖研究。