BACKGROUND AND PURPOSE

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.

EXPERIMENTAL APPROACH

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.

KEY RESULTS

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.

CONCLUSION AND IMPLICATIONS

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.

LINKED ARTICLES

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.