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


METHODS
Prospective, controlled, randomized animal study.


METHODS
A research institute laboratory.


METHODS
Male, adult Sprague-Dawley rats.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Sprague
Jon E
JE
Department of Pharmaceutical & Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada, OH, USA.
Moze
Petra
P
Caden
David
D
Rusyniak
Daniel E
DE
Holmes
Courtney
C
Goldstein
David S
DS
Mills
Edward M
EM
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D002395:Catecholamines / Q000097:blood; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000506:poisoning*; D009638:Norepinephrine / Q000097:blood; D011412:Propanolamines / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012206:Rhabdomyolysis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D002395:Catecholamines; D011412:Propanolamines; D000077261:Carvedilol; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009638:Norepinephrine