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Dissociation between hypothermia and neurotoxicity caused by mephedrone and methcathinone in TPH2 knockout mice

  • John H. Anneken
  • Mariana Angoa-Perez
  • Girish C. Sati
  • David Crich
  • Donald M. Kuhn
Original Investigation

Abstract

Rationale

Mephedrone is a commonly abused constituent of “bath salts” and has many pharmacological effects in common with methamphetamine. Despite their structural similarity, mephedrone differs significantly from methamphetamine in its effects on core body temperature and dopamine nerve endings. The reasons for these differences remain unclear.

Objectives

Mephedrone elicits a transient hypothermia which may provide intrinsic neuroprotection against methamphetamine-like toxicity to dopamine nerve endings. Furthermore, evidence in the literature suggests that this hypothermia is mediated by serotonin. By utilizing transgenic mice devoid of brain serotonin, we determined the contribution of this neurotransmitter to changes in core body temperature as well as its possible role in protecting against neurotoxicity. The effects of methcathinone and 4-methyl-methamphetamine, two structural analogs of mephedrone and methamphetamine, were also evaluated in these mice.

Results

The hypothermia induced by mephedrone and methcathinone in wild-type mice was not observed in mice lacking brain serotonin. Despite preventing drug-induced hypothermia, the lack of serotonin did not alter the neurotoxic profiles of the test drugs.

Conclusions

Serotonin is a key mediator of pharmacological hypothermia induced by mephedrone and methcathinone, but these body temperature effects do not contribute to dopamine nerve ending damage observed in mice following treatment with mephedrone, methcathinone or 4-methyl-methamphetamine. Thus, the key component of methamphetamine neurotoxicity lacking in mephedrone remains to be elucidated.

Keywords

Mephedrone Methcathinone 4-methyl-methamphetamine Dopamine Hypothermia Neurotoxicity 

Notes

Acknowledgements

We thank Dr. Roxanne Vaughn for her generous gift of DAT antibodies. We would also like to thank the NIDA Drug Supply Program for providing mephedrone and methcathinone for use in these studies.

Funding information

This research was supported by a grant from the National Institute on Drug Abuse (R21 DA0396671).

Compliance with ethical standards

All procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee at Wayne State University.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Research & Development ServiceJohn D. Dingell VA Medical Center, R&D Service (11R)DetroitUSA
  2. 2.Department of Psychiatry and Behavioral NeurosciencesWayne State University School of MedicineDetroitUSA
  3. 3.Department of ChemistryWayne State UniversityDetroitUSA

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