Moreira Fabricio A, Jupp Bianca, Belin David, Dalley Jeffrey W
aDepartment of Pharmacology, Institute of Biological Science, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Departments of bPsychology cPharmacology, University of Cambridge dDepartment of Psychiatry, Addenbrookes's Hospital University of Cambridge, Cambridge, UK.
Behav Pharmacol. 2015 Feb;26(1-2):59-72. doi: 10.1097/FBP.0000000000000109.
Since the identification and cloning of the major cannabinoid receptor expressed in the brain almost 25 years ago research has highlighted the potential of drugs that target the endocannabinoid system for treating addiction. The endocannabinoids, anandamide and 2-arachidonoyl glycerol, are lipid-derived metabolites found in abundance in the basal ganglia and other brain areas innervated by the mesocorticolimbic dopamine systems. Cannabinoid CB1 receptor antagonists/inverse agonists reduce reinstatement of responding for cocaine, alcohol and opiates in rodents. However, compounds acting on the endocannabinoid system may have broader application in treating drug addiction by ameliorating associated traits and symptoms such as impulsivity and anxiety that perpetuate drug use and interfere with rehabilitation. As a trait, impulsivity is known to predispose to addiction and facilitate the emergence of addiction to stimulant drugs. In contrast, anxiety and elevated stress responses accompany extended drug use and may underlie the persistence of drug intake in dependent individuals. In this article we integrate and discuss recent findings in rodents showing selective pharmacological modulation of impulsivity and anxiety by cannabinoid agents. We highlight the potential of selective inhibitors of endocannabinoid metabolism, directed at fatty acid amide hydrolase and monoacylglycerol lipase, to reduce anxiety and stress responses, and discuss novel mechanisms underlying the modulation of the endocannabinoid system, including the attenuation of impulsivity, anxiety, and drug reward by selective CB2 receptor agonists.
大约25年前，大脑中主要大麻素受体被鉴定和克隆出来，此后的研究凸显了靶向内源性大麻素系统的药物在治疗成瘾方面的潜力。内源性大麻素，如花生四烯乙醇胺和2-花生四烯酸甘油酯，是在基底神经节以及中脑边缘多巴胺系统支配的其他脑区大量存在的脂质衍生代谢物。大麻素CB1受体拮抗剂/反向激动剂可减少啮齿动物对可卡因、酒精和阿片类药物反应的复燃。然而，作用于内源性大麻素系统的化合物可能在治疗药物成瘾方面有更广泛的应用，通过改善诸如冲动和焦虑等相关特征和症状，这些特征和症状会使药物使用持续存在并干扰康复。作为一种特征，冲动已知会使人易患成瘾并促进对兴奋剂药物成瘾的出现。相比之下，焦虑和应激反应增强伴随长期药物使用，可能是依赖个体持续药物摄入的基础。在本文中，我们整合并讨论了啮齿动物的最新研究结果，这些结果表明大麻素类药物对冲动和焦虑有选择性药理调节作用。我们强调了针对脂肪酸酰胺水解酶和单酰甘油脂肪酶的内源性大麻素代谢选择性抑制剂在减轻焦虑和应激反应方面的潜力，并讨论了内源性大麻素系统调节的新机制，包括选择性CB2受体激动剂对冲动、焦虑和药物奖赏的减弱作用。
