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Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.
Neuropsychopharmacology 2016; 41(2):549-59N

Abstract

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.

Authors+Show Affiliations

National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore, MD, USA.National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore, MD, USA.National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore, MD, USA.National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore, MD, USA.National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore, MD, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

26105141

Citation

Kiyatkin, Eugene A., et al. "Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated By Social Interaction." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 41, no. 2, 2016, pp. 549-59.
Kiyatkin EA, Ren S, Wakabayashi KT, et al. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction. Neuropsychopharmacology. 2016;41(2):549-59.
Kiyatkin, E. A., Ren, S., Wakabayashi, K. T., Baumann, M. H., & Shaham, Y. (2016). Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 41(2), pp. 549-59. doi:10.1038/npp.2015.182.
Kiyatkin EA, et al. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated By Social Interaction. Neuropsychopharmacology. 2016;41(2):549-59. PubMed PMID: 26105141.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction. AU - Kiyatkin,Eugene A, AU - Ren,Suelynn, AU - Wakabayashi,Ken T, AU - Baumann,Michael H, AU - Shaham,Yavin, Y1 - 2015/06/24/ PY - 2015/04/16/received PY - 2015/06/02/revised PY - 2015/06/17/accepted PY - 2015/6/25/entrez PY - 2015/6/25/pubmed PY - 2016/9/22/medline SP - 549 EP - 59 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 41 IS - 2 N2 - 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. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/26105141/Clinically_Relevant_Pharmacological_Strategies_That_Reverse_MDMA_Induced_Brain_Hyperthermia_Potentiated_by_Social_Interaction_ L2 - http://dx.doi.org/10.1038/npp.2015.182 DB - PRIME DP - Unbound Medicine ER -