Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2016-01, Vol.41 (2), p.549-559
• Main Authors: Kiyatkin, Eugene A, Ren, Suelynn, Wakabayashi, Ken T, Baumann, Michael H, Shaham, Yavin
• Format: Article
• Language: English
• Subjects: Adrenergic receptors; Animals; Antipsychotic Agents - pharmacology; Body Temperature - drug effects; Brain - drug effects; Brain - physiopathology; Carbazoles - pharmacology; Clozapine - pharmacology; Drug dosages; Drug use; Emergency medical care; Fever; Fever - chemically induced; Fever - drug therapy; Fever - physiopathology; Hallucinogens - adverse effects; Hallucinogens - pharmacology; Heat; Homeostasis - drug effects; Homeostasis - physiology; Hyperthermia; Intoxication; Labetalol - pharmacology; Laboratory animals; Lifesaving; Male; Metabolism; N-Methyl-3,4-methylenedioxyamphetamine - adverse effects; N-Methyl-3,4-methylenedioxyamphetamine - pharmacology; Original; Physiology; Propanolamines - pharmacology; Rats, Long-Evans; Skin; Skin - drug effects; Skin - physiopathology; Social Behavior; Social interaction; Surgery; Sympathomimetics - pharmacology; Temperature effects; Vasodilator Agents - pharmacology
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2015.182

MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.