Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
Pharmacol Biochem Behav. 2011 Mar;98(1):21-7. doi: 10.1016/j.pbb.2010.12.002. Epub 2010 Dec 8.
Cannabinoids have long been shown to have a range of potential therapeutic effects, including antiemetic actions, analgesia, and anxiolysis. However, psychomimetic and memory disruptive side effects, as well as the potential for abuse and dependence, have restricted their clinical development. Endogenous cannabinoids (i.e., endocannabinoids; eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced throughout the limbic system and other brain regions associated with emotionality and are believed to modulate behavioral responses to stress-related conditions. AEA and 2-AG are rapidly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Accordingly, inhibition of each enzyme increases brain levels of the appropriate eCB. Although FAAH inhibition has been established to decrease anxiety-like behavior, the role of 2-AG has been difficult to ascertain until the recent synthesis of JZL184, a potent and selective MAGL inhibitor. In the present study, we investigated the effects of inhibiting FAAH or MAGL on anxiety-like behavior in marble burying, a model of repetitive, compulsive behaviors germane to anxiety disorders such as obsessive-compulsive disorder. The FAAH inhibitor PF-3845, the MAGL inhibitor JZL184, and the benzodiazepine diazepam decreased marble burying at doses that did not affect locomotor activity. In contrast, Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, did not consistently reduce marble burying without also eliciting profound decreases in locomotor behavior. The CB1 cannabinoid receptor antagonist rimonabant blocked the reduction in marble burying caused by FAAH and MAGL inhibitors, but not by diazepam, indicating a CB1 receptor mechanism of action. These data indicate that elevation of AEA or 2-AG reduces marble burying behavior and suggest that their catabolic enzymes represent potential targets for the development of new classes of pharmacotherapeutics to treat anxiety-related disorders.
大麻素具有广泛的潜在治疗效果，包括止吐作用、镇痛作用和焦虑缓解作用。然而，致幻和记忆干扰副作用，以及滥用和依赖的可能性，限制了它们的临床开发。内源性大麻素（即内源性大麻素；eCBs），如花生四烯酸乙醇酰胺（AEA）和 2-花生四烯酸甘油（2-AG），在边缘系统和其他与情绪相关的大脑区域产生，被认为可以调节对与应激相关的条件的行为反应。AEA 和 2-AG 被各自的酶脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）迅速代谢。因此，抑制每种酶都会增加适当的 eCB 脑内水平。尽管已经证实 FAAH 抑制可降低焦虑样行为，但直到最近合成了强效和选择性 MAGL 抑制剂 JZL184，2-AG 的作用才难以确定。在本研究中，我们研究了抑制 FAAH 或 MAGL 对强迫性埋珠行为（一种与强迫症等焦虑障碍相关的重复性强迫行为模型）中焦虑样行为的影响。FAAH 抑制剂 PF-3845、MAGL 抑制剂 JZL184 和苯二氮䓬类药物地西泮可降低剂量而不影响运动活动的埋珠行为。相比之下，大麻的主要精神活性成分 Δ9-四氢大麻酚（THC）在不引起运动行为明显减少的情况下，并不总是减少埋珠行为。CB1 大麻素受体拮抗剂利莫那班阻断了 FAAH 和 MAGL 抑制剂引起的埋珠减少，但不阻断地西泮引起的埋珠减少，表明存在 CB1 受体作用机制。这些数据表明，AEA 或 2-AG 的升高可减少埋珠行为，并表明其代谢酶可能是开发治疗焦虑相关疾病的新类别的药物治疗的潜在靶点。
