Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Br J Pharmacol. 2019 May;176(10):1541-1551. doi: 10.1111/bph.14473. Epub 2018 Sep 14.
The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) bind to CB and CB cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB receptor antagonism and CB receptor activation are known to inhibit certain effects of cocaine, they have been investigated separately. Here, we tested the hypothesis that there is a reciprocal interaction between CB receptor blockade and CB receptor activation in modulating behavioural responses to cocaine.
Male Swiss mice received i.p. injections of cannabinoid-related drugs followed by cocaine, and were then tested for cocaine-induced hyperlocomotion, c-Fos expression in the nucleus accumbens and conditioned place preference. Levels of endocannabinoids after cocaine injections were also analysed.
The CB receptor antagonist, rimonabant, and the CB receptor agonist, JWH133, prevented cocaine-induced hyperlocomotion. The same results were obtained by combining sub-effective doses of both compounds. The CB receptor antagonist, AM630, reversed the inhibitory effects of rimonabant in cocaine-induced hyperlocomotion and c-Fos expression in the nucleus accumbens. Selective inhibitors of anandamide and 2-AG hydrolysis (URB597 and JZL184, respectively) failed to modify this response. However, JZL184 prevented cocaine-induced hyperlocomotion when given after a sub-effective dose of rimonabant. Cocaine did not change brain endocannabinoid levels. Finally, CB receptor blockade reversed the inhibitory effect of rimonabant in the acquisition of cocaine-induced conditioned place preference.
The present data support the hypothesis that CB and CB receptors work in concert with opposing functions to modulate certain addiction-related effects of cocaine.
This article is part of a themed section on 8 European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.
内源性大麻素大麻素和 2-花生四烯酰甘油（2-AG）与大脑中的 CB 和 CB 大麻素受体结合，并调节中脑边缘多巴胺能通路。该神经回路被包括可卡因在内的精神兴奋剂药物所利用。尽管已经知道 CB 受体拮抗剂和 CB 受体激动剂可抑制可卡因的某些作用，但它们是分别进行研究的。在这里，我们测试了这样一种假设，即在调节可卡因引起的行为反应方面，CB 受体阻断和 CB 受体激活之间存在相互作用。
雄性瑞士小鼠接受腹腔内注射大麻素相关药物，然后给予可卡因，并检测可卡因诱导的过度运动、伏隔核中的 c-Fos 表达和条件性位置偏好。还分析了可卡因注射后内源性大麻素的水平。
CB 受体拮抗剂利莫那班和 CB 受体激动剂 JWH133 可预防可卡因引起的过度运动。两种化合物的亚有效剂量联合使用也可获得相同的结果。CB 受体拮抗剂 AM630 逆转了 AM630 在可卡因诱导的过度运动和伏隔核中 c-Fos 表达中的抑制作用。选择性的花生四烯酸和 2-AG 水解抑制剂（URB597 和 JZL184）分别未能改变此反应。然而，JZL184 在给予亚有效剂量的利莫那班后可预防可卡因引起的过度运动。可卡因并未改变脑内源性大麻素水平。最后，CB 受体阻断逆转了利莫那班在可卡因诱导的条件性位置偏好获得中的抑制作用。
本数据支持这样一种假设，即 CB 和 CB 受体协同作用，具有相反的功能，以调节可卡因的某些与成瘾相关的作用。
本文是关于 8 欧洲大麻素研究研讨会的专题部分的一部分。要查看本节中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc。
