Clozapine reverses increased brown adipose tissue thermogenesis induced by 3,4-methylenedioxymethamphetamine and by cold exposure in conscious rats.
W W Blessing, A Zilm, Y Ootsuka
Neuroscience September 15, 2006 DOI: 10.1016/j.neuroscience.2006.05.050 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Sample size | 7 |
| Population | Conscious rats |
| Interventions | MDMA (3 Clozapine Cold exposure |
| Duration | 90 minutes after MDMA; 60 minutes after clozapine or vehicle |
| Topics | MDMA |
| Key findings | MDMA increased iBAT temperature by 1.7 degrees C at 90 minutes, and clozapine reversed this increase by 1.3 degrees C within 60 minutes, while also reducing stress- and cold-induced iBAT warming. The authors suggest MDMA activates sympathetic thermoregulatory pathways shared with cold defense and stress responses, and propose clozapine's inhibition of iBAT thermogenesis may relate to its tendency to cause obesity and to its potential use against MDMA-induced hyperthermia. |
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 6
- The role of monoamines in the changes in body temperature induced by 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) and its derivatives British Journal of Pharmacology March 3, 2010
- Differential effects of cathinone compounds andMDMAon body temperature in the rat, and pharmacological characterization of mephedrone‐induced hypothermia British Journal of Pharmacology October 8, 2012
- Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions Critical Reviews in Toxicology October 3, 2012
- Treadmill running restores MDMA-mediated hyperthermia prevented by inhibition of the dorsomedial hypothalamus. Brain Research May 22, 2015
- MDMA: interactions with other psychoactive drugs. Pharmacology, Biochemistry, and Behavior October 2011
and 1 more in the library
Cites 8
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- The pharmacology of the acute hyperthermic response that follows administration of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to rats British Journal of Pharmacology 2002
- Methylenedioxymethamphetamine-induced hyperthermia and neurotoxicity are independently mediated by 5-HT2 receptors Brain Research October 1, 1990
- Cutaneous Vasoconstriction Contributes to Hyperthermia Induced by 3,4-Methylenedioxymethamphetamine (Ecstasy) in Conscious Rabbits Journal of Neuroscience November 1, 2001
- Studies on the effect of MDMA (‘ecstasy’) on the body temperature of rats housed at different ambient room temperatures British Journal of Pharmacology July 4, 2005
and 3 more in the library