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

Abstract 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.