Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model*

Abstract

Hyperthermia is a potentially fatal manifestation of severe 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) intoxication. No proven effective drug treatment exists to reverse this potentially life-threatening hyperthermia, likely because mechanisms of peripheral thermogenesis are poorly understood. Using a rat model of MDMA hyperthermia, we evaluated the acute drug-induced changes in plasma catecholamines and used these results as a basis for the selection of drugs that could potentially reverse this hyperthermia. Prospective, controlled, randomized animal study. A research institute laboratory. Male, adult Sprague-Dawley rats. Based on MDMA-induced changes in plasma catecholamine levels, rats were subjected to the nonselective (beta1 + beta2) adrenergic receptor antagonists propranolol or nadolol or the alpha1- + beta1,2,3-adrenergic receptor antagonist carvedilol before or after a thermogenic challenge of MDMA. Plasma catecholamines levels 30 mins after MDMA (40 mg/kg, subcutaneously) were determined by high-pressure liquid chromatography and electrochemical detection. Core temperature was measured by a rectal probe attached to a thermocouple. Four hours after MDMA treatment, blood was drawn and serum creatine kinase levels were measured as a marker of rhabdomyolysis using a Vitros analyzer. MDMA induced a 35-fold increase in norepinephrine levels, a 20-fold increase in epinephrine, and a 2.4-fold increase in dopamine levels. Propranolol (10 mg/kg, intraperitoneally) or nadolol (10 mg/kg, intraperitoneally) administered 30 mins before MDMA had no effect on the thermogenic response. In contrast, carvedilol (5 mg/kg, intraperitoneally) administered 15 mins before or after MDMA prevented this hyperthermic response. Moreover, when administered 1 hr after MDMA, carvedilol completely reversed established hyperthermia and significantly attenuated subsequent MDMA-induced creatine kinase release. These data show that alpha1 and beta3-adrenergic receptors may contribute to the mediation of MDMA-induced hyperthermia and that drugs targeting these receptors, such as carvedilol, warrant further investigation as novel therapies for the treatment of psychostimulant-induced hyperthermia and its sequelae.