Endocannabinoid modulation of affective signs of cannabinoid withdrawal

说明(申请人提供)：大麻是全世界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较轻的“软性毒品”。然而，正如DSM-V最近承认的那样，大麻使用障碍和大麻戒断综合症影响到许多吸毒者，主要症状是焦虑、激动和对大麻的渴望增加。毫不奇怪，缓解禁欲带来的厌恶症状是复发的常见原因。因此，有必要开发新的大麻依赖治疗方法。拟议研究的目标是为人类大麻素依赖的临床治疗提供信息。目前关于大麻依赖的临床前研究使用躯体结果来量化大麻戒断。尽管这些模型非常有用，但它们没有探索大麻戒断的情感方面，这些方面在人类中最突出，并直接导致复发。我们的初步数据表明，戒掉大麻的主要精神活性成分�四氢大麻酚会增加对亮/暗盒子黑暗部分的偏好，并减少大理石掩埋，这是挖掘的替代指标。目标1的目标是充分描述这些情绪性的变化。我们将反复用THC治疗小鼠，然后用大麻素受体拮抗剂利莫那班催促戒断，以在一系列众所周知的对抗焦虑药物有反应的测试中诱导和量化戒断行为。除了行为干预外，辅助疗法在减少药物依赖方面也取得了很大成功。拟议研究的目标2是通过阻断内源性大麻素的代谢来使戒断诱导的行为变化正常化。这两种内源性大麻素为双胺，在体内主要由脂肪酸酰胺水解酶(FAAH)和2-花生四烯基乙醇胺(2-花生四烯基乙醇胺)代谢，主要由单酰甘油脂肪酶(MAGL)代谢。我们建议选择性地抑制THC戒断小鼠的FAAH或MAGL，并测试行为分析的变化，我们未发表的初步数据表明，THC戒断会改变这些变化。可以预期，抑制FAAH或MAGL将减轻戒断诱导的行为改变，而对一般活动没有任何影响。拟议项目的成功完成预计将为更大规模的神经/行为项目提供初步数据，该项目的目标将是为人类大麻类药物依赖研究提供信息。

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.