Envolvimento do sistema endocanabinoide sobre os efeitos comportamentais e moleculares induzidos pela cocaína

Abstract

Endocannabinoids anandamide and 2-arachidonoylglycerol (2AG) act on cannabinoid receptors type 1 (CB1) and type 2 (CB2), through which they modulate the mesolimbic dopaminergic pathway. This neurocircuitry is an important target for abuse drugs, including cocaine. Accordingly, antagonism of CB1 receptor as well as activation of CB2 inhibit several effects of this psychostimulant. However, a reciprocal interaction between these cannabinoid receptors has not been investigated. In this context, we tested the hypothesis that blockade of CB1 would displace the actions of endocannabinoids (anandamide and 2-AG) towards CB2 receptors, inhibiting the actions of cocaine. Initially we observed that rimonabant, a CB1 antagonist, prevented hyperlocomotion, increase in c-Fos protein expression in the nucleus accumbens and the ERK phosphorylation in striatum induced by cocaine. Supporting our hypothesis, pretreatment with a CB2 antagonist (AM-630), reversed this inhibitory effect of rimonabant on these responses. Furthermore, combination of a sub-effective dose of rimonabant and a CB2 agonist (JWH-133) also prevented cocaine-induced hyperlocomotion. Inhibitors of anandamide hydrolysis (URB-597) and 2-AG (JZL184) did not change this effect. However, when combined with a sub-effective dose of rimonabant, JZL184 (but not URB597) prevented hyperlocomotion. This result suggests the involvement of 2-AG in modulation of cocaine-response, although the endocannabinoid levels in limbic regions have not been modified by this drug. Finally, also in accordance with the tested hypothesis, CB2 blockade reversed the inhibitory effect of rimonabant on the acquisition of cocaine-induced conditioned place preference. In conclusion, our data suggest a possible mechanism through which modulation in the endocannabinoid system regulates cocaine-responses.