Opposite effects of cannabinoid CB 1 and CB 2 receptors on antipsychotic clozapine-induced cardiotoxicity

Abstract

Background and Purpose: Clozapine is an atypical antipsychotic drug that is very efficacious in treating psychosis, but the risk of severe cardiotoxicity limits its clinical use. The present study investigated the harmful effects of clozapine on myocardium and assessed the involvement of cannabinoid receptors in its cardiotoxicity. Experimental Approach: Clozapine alone or in combination with selective cannabinoid receptor antagonists or agonists were used to treat mice and cardiomyocytes. Key Results: Clozapine induced myocardial inflammation and infiltration 7 days after i.p. injection. Mice survival rate and myocardial infiltration, and fibrotic lesions were dose-dependently worsened by clozapine. Clozapine decreased major endocannabinoid levels in sera and cultured cardiomyocytes. Cannabinoid CB 1 receptors decreased in clozapine-treated hearts and were translocated from cytomembranes to cytoplasm and nuclei, whereas CB 2 receptors increased in clozapine-treated hearts and inversely translocated from nuclei to the cytomembrane. Selective antagonists of CB 1 receptors, rimonabant and AM281, but not its selective agonist arachidonyl-2′-chloroethylamide, ameliorated clozapine-induced myocardial inflammatory infiltration and fibrotic lesions. In contrast, selective agonists of CB 2 receptors, AM1241 and JWH-133, but not its selective antagonist AM630, blunted clozapine-mediated cardiotoxicity in mice. In cultured cardiomyocytes, clozapine increased the pro-inflammatory factor IL-1β and the concentrations of myocardial injury markers (LDH and aspartate aminotransferase); these effects were reversed by either a CB 1 antagonist or CB 2 agonist and further prevented by combined pretreatments. Conclusions and Implications: Our data provide evidence that cannabinoid CB 1 and CB 2 receptors have opposite effects and selective antagonists of CB 1 or agonists of CB 2 receptors might confer protective effects against clozapine in myocardium.