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This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB<jats:sub>1<\/jats:sub>receptor antagonism and CB<jats:sub>2<\/jats:sub>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<jats:sub>1<\/jats:sub>receptor blockade and CB<jats:sub>2<\/jats:sub>receptor activation in modulating behavioural responses to cocaine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Male Swiss mice received i.p. injections of cannabinoid\u2010related drugs followed by cocaine, and were then tested for cocaine\u2010induced hyperlocomotion, c\u2010Fos expression in the nucleus accumbens and conditioned place preference. Levels of endocannabinoids after cocaine injections were also analysed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The CB<jats:sub>1<\/jats:sub>receptor antagonist, rimonabant, and the CB<jats:sub>2<\/jats:sub>receptor agonist, JWH133, prevented cocaine\u2010induced hyperlocomotion. The same results were obtained by combining sub\u2010effective doses of both compounds. The CB<jats:sub>2<\/jats:sub>receptor antagonist, AM630, reversed the inhibitory effects of rimonabant in cocaine\u2010induced hyperlocomotion and c\u2010Fos expression in the nucleus accumbens. Selective inhibitors of anandamide and 2\u2010AG hydrolysis (URB597 and JZL184, respectively) failed to modify this response. However, JZL184 prevented cocaine\u2010induced hyperlocomotion when given after a sub\u2010effective dose of rimonabant. Cocaine did not change brain endocannabinoid levels. Finally, CB<jats:sub>2<\/jats:sub>receptor blockade reversed the inhibitory effect of rimonabant in the acquisition of cocaine\u2010induced conditioned place preference.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>The present data support the hypothesis that CB<jats:sub>1<\/jats:sub>and CB<jats:sub>2<\/jats:sub>receptors work in concert with opposing functions to modulate certain addiction\u2010related effects of cocaine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on 8<jats:sup>th<\/jats:sup>European Workshop on Cannabinoid Research. To view the other articles in this section visit<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v176.10\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v176.10\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14473","type":"journal-article","created":{"date-parts":[[2018,8,13]],"date-time":"2018-08-13T02:04:35Z","timestamp":1534125875000},"page":"1541-1551","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Opposing roles of CB<sub>1<\/sub>and CB<sub>2<\/sub>cannabinoid receptors in the stimulant and rewarding effects of cocaine"],"prefix":"10.1111","volume":"176","author":[{"given":"Pedro H","family":"Gobira","sequence":"first","affiliation":[{"name":"Department of Pharmacology Institute of Biological Sciences, Universidade Federal de Minas Gerais Belo Horizonte MG 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