The effects of cannabinoid CB1, CB2 and vanilloid TRPV1 receptor antagonists on cocaine addictive behavior in rats

There is evidence that indicates that tonic activation of cannabinoid CB1 receptors plays a role in extinction/reinstatement of cocaine seeking-behavior but is not involved in the maintenance of cocaine self-administration. To further explore the importance of other endocannabinoid-related receptors in an animal model of cocaine addiction, the present paper examines cannabinoid CB2 receptor antagonist N-((1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) and the transient receptor potential vanilloid type-1 (TRPV1) receptor antagonist N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) on intravenous (i.v.) cocaine self-administration and extinction/reinstatement of cocaine-seeking behavior in rats. For comparison and reference purposes, the effect of the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) was also examined. Moreover, for comparison effects of those drugs on operant lever responding for artificial (cocaine) vs. natural (food) reward, food self-administration was also evaluated. Our findings show that AM251 (1–3 mg/kg), SR144528 (0.1–1 mg/kg) and SB366791 (0.3–1 mg/kg) did not affect cocaine self-administration. However, AM251 (0.1–1 mg/kg), SR144528 (0.1–1 mg/kg) and SB366791 (0.1–1 mg/kg) decreased cocaine-induced reinstatement of cocaine-seeking behavior, and AM251 (0.3–1 mg/kg) decreased cue-induced reinstatement. Moreover, AM251 (3 mg/kg), SR144528 (0.1–1 mg/kg) and SB366791 (0.1–1 mg/kg) slightly decreased food self-administration behavior, but only AM251 (3 mg/kg) reduced food reward. In conclusion, our results indicate for the first time, that tonic activation of CB2 or TRPV1 receptors is involved in cocaine-induced reinstatement of cocaine-seeking behavior, but their activity is not necessary for the rewarding effect of this psychostimulant. In contrast to CB1 receptors, neither CB2 nor TRPV1 receptors play a role in cue-induced reinstatement of cocaine-seeking behavior.

► Tonic CB1, CB2, and TRPV1 receptor activation is not necessary for cocaine reward.
► CB1, CB2 and TRPV1 receptor antagonists inhibit cocaine-induced reinstatement.
► CB1 receptor antagonist inhibits drug-associated cue-induced reinstatement.
► Operant response for food intake after CB1, CB2 or TRPV1 receptor antagonists was reduced.