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Dantrolene sodium fails to reverse robust brain hyperthermia induced by MDMA and methamphetamine in rats

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Abstract

Rationale

Hyperthermia induced by psychomotor stimulants may cause leakage of the blood-brain barrier, vasogenic edema, and lethality in extreme cases. Current treatments such as whole-body cooling are only symptomatic and a clear need to develop pharmacological interventions exists. Dantrolene sodium, a peripheral muscle relaxant used in the treatment of malignant hyperthermia, has been proposed as potentially effective to treat MDMA-hyperthermia in emergency rooms. However, debate around its efficacy for this indication persists.

Objectives

To investigate dantrolene as a treatment for illicit hyperthermia induced by psychomotor stimulant drugs, we examined how Ryanodex®, a concentrated formulation of dantrolene sodium produced by Eagle Pharmaceuticals, influences 3,4-methylenedioxymethamphetamine (MDMA)- and methamphetamine (METH)-induced hyperthermia in awake freely moving rats. We injected rats with moderate doses of MDMA (9 mg/kg) and METH (9 mg/kg) and administered Ryanodex® intravenously (6 mg/kg) after the development of robust hyperthermia (>2.5 °C) mimicking clinical acute intoxication. We conducted simultaneous temperature recordings in the brain, temporal muscle, and skin to determine the basic mechanisms underlying temperature responses. To assess the efficacy of dantrolene in attenuating severe hyperthermia, we administered MDMA to rats maintained in a warm ambient environment (29 °C), conditions which produce robust brain and body hyperthermia (>40 °C) and lethality.

Results

Dantrolene failed to attenuate MDMA- and METH-induced hyperthermia, though locomotor activity was significantly reduced. All animals maintained at warm ambient temperatures that received dantrolene during severe drug-induced hyperthermia died within or soon after the recording session.

Conclusions

Our results suggest that dantrolene sodium formulations are not mechanistically suited to treat MDMA- and METH-induced hyperthermia.

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Abbreviations

ANOVA:

Analysis of variance

iv:

Intravenous

MDMA:

3,4-Methylenedioxymethamphetamine

METH:

Methamphetamine

NAc:

Nucleus accumbens

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Acknowledgements

We would like to acknowledge the contributions of Dr. Adrian Hepner and Eagle Pharmaceuticals in assisting in the design of and providing partial financial support for this study. We also want to thank Dr. Michael Greenberg for kind suggestions regarding the matters discussed in this manuscript.

Funding

The study was supported by the Intramural Research Program of the NIH, NIDA (# 1ZIA DA000566-13 for EAK).

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Authors and Affiliations

  1. Behavioral Neuroscience Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, DHHS, 251 Bayview Blvd, Baltimore, MD, 21224, USA

    Keaton T. Cameron-Burr, R. Aaron Bola & Eugene A. Kiyatkin

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  1. Keaton T. Cameron-Burr
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  2. R. Aaron Bola
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  3. Eugene A. Kiyatkin
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Correspondence to Eugene A. Kiyatkin.

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Cameron-Burr, K.T., Bola, R.A. & Kiyatkin, E.A. Dantrolene sodium fails to reverse robust brain hyperthermia induced by MDMA and methamphetamine in rats. Psychopharmacology 240, 785–795 (2023). https://doi.org/10.1007/s00213-023-06321-x

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  • DOI: https://doi.org/10.1007/s00213-023-06321-x

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