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

Jon E. Sprague, Petra Moze, David Caden, Daniel Rusyniak, Courtney Holmes, David S. Goldstein, Edward M. Mills

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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. Design: Prospective, controlled, randomized animal study. Setting: A research institute laboratory. Subjects: Male, adult Sprague-Dawley rats. Interventions: Based on MDMA-induced changes in plasma catecholamine levels, rats were subjected to the nonselective (β1 + β2) adrenergic receptor antagonists propranolol or nadolol or the α1- + β1,2,3-adrenergic receptor antagonist carvedilol before or after a thermogenic challenge of MDMA. Measurement and Main 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. Conclusion: These data show that α1 and β3-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 seperthermia quelae.

Original languageEnglish
Pages (from-to)1311-1316
Number of pages6
JournalCritical Care Medicine
Volume33
Issue number6
DOIs
StatePublished - Jun 2005

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N-Methyl-3,4-methylenedioxyamphetamine
Rhabdomyolysis
Fever
Animal Models
Nadolol
Catecholamines
Induced Hyperthermia
Adrenergic Antagonists
Creatine Kinase
Propranolol
carvedilol
Pharmaceutical Preparations
Drug Receptors
Thermogenesis
Drug Delivery Systems
Adrenergic Receptors
Epinephrine
Sprague Dawley Rats

Keywords

  • α- and β-adrenergic receptors
  • 3,4-methylenedioxymethamphetamine
  • Carvedilol
  • Creatine kinase
  • Hyperthermia
  • Norepinephrine

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model. / Sprague, Jon E.; Moze, Petra; Caden, David; Rusyniak, Daniel; Holmes, Courtney; Goldstein, David S.; Mills, Edward M.

In: Critical Care Medicine, Vol. 33, No. 6, 06.2005, p. 1311-1316.

Research output: Contribution to journalArticle

Sprague, Jon E. ; Moze, Petra ; Caden, David ; Rusyniak, Daniel ; Holmes, Courtney ; Goldstein, David S. ; Mills, Edward M. / Carvedilol reverses hyperthermia and attenuates rhabdomyolysis induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in an animal model. In: Critical Care Medicine. 2005 ; Vol. 33, No. 6. pp. 1311-1316.
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AU - Moze, Petra

AU - Caden, David

AU - Rusyniak, Daniel

AU - Holmes, Courtney

AU - Goldstein, David S.

AU - Mills, Edward M.

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N2 - 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. Design: Prospective, controlled, randomized animal study. Setting: A research institute laboratory. Subjects: Male, adult Sprague-Dawley rats. Interventions: Based on MDMA-induced changes in plasma catecholamine levels, rats were subjected to the nonselective (β1 + β2) adrenergic receptor antagonists propranolol or nadolol or the α1- + β1,2,3-adrenergic receptor antagonist carvedilol before or after a thermogenic challenge of MDMA. Measurement and Main 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. Conclusion: These data show that α1 and β3-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 seperthermia quelae.

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