Clozapine reverses increased brown adipose tissue thermogenesis induced by 3,4-methylenedioxymethamphetamine and by cold exposure in conscious rats

Abstract

Clozapine, an atypical antipsychotic agent important for the treatment of schizophrenia, has marked inhibitory effects on sympathetic outflow to the thermoregulatory cutaneous circulation. In rabbits clozapine reverses ear pinna vasoconstriction induced either by administration of MDMA (3,4-methylenedioxymethamphetamine, ecstasy) or by exposing the animal to a cold environment. In rats, both these procedures are known to increase sympathetic activation of interscapular brown adipose tissue (iBAT) thermogenesis, important for heat production in the rat. In the present study in conscious rats we determined whether clozapine reduces iBAT thermogenesis induced by MDMA and by exposure to cold. We designed our study so that we could also determine effects of clozapine on the acute (stress-induced) increases in iBAT thermogenesis initiated by the process of s.c. injection. MDMA increased iBAT temperature (+1.7+/-0.2 degrees C after 90 min, P<0.01, n=14 measurements from seven rats each studied on two occasions). Clozapine acutely reversed the MDMA-elicited increase in iBAT temperature (-1.3+/-0.2 degrees C 60 min after clozapine treatment following MDMA versus +0.3+/-0.2 degrees C for 60 min after vehicle treatment following MDMA, P<0.01, n=7). Clozapine also reduced stress-induced increases in iBAT temperature, as well as increases elicited by exposing rats to a cold (5 degrees C) environment. Results, taken together with our previous findings, suggest that MDMA activates the sympathetic thermoregulatory outputs (including the output to iBAT) that defend body temperature against cold exposure and that increase body temperature in response to environmental stress. Clozapine's marked inhibition of iBAT thermogenesis may provide a clue to its marked tendency to cause obesity when used to treat humans with mental disorders including schizophrenia. Our demonstration in rats that clozapine decreases sympathetically-mediated increases in iBAT temperature elicited by MDMA adds to the likelihood that clozapine and clozapine-like agents might be therapeutically effective in life threatening hyperthermia induced by MDMA in humans.