Psychopharmacology

, Volume 231, Issue 14, pp 2771–2783

Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

Authors

    • Research Service (R&D22), VA Medical Center
    • Departments of Psychiatry and Behavioral NeuroscienceOregon Health and Science University
    • The Methamphetamine Abuse Research CenterOregon Health and Science University
  • Amy J. Eshleman
    • Research Service (R&D22), VA Medical Center
    • Departments of Psychiatry and Behavioral NeuroscienceOregon Health and Science University
  • Robert A. Johnson
    • Research Service (R&D22), VA Medical Center
    • Departments of Psychiatry and Behavioral NeuroscienceOregon Health and Science University
  • Katherine M. Wolfrum
    • Departments of Psychiatry and Behavioral NeuroscienceOregon Health and Science University
  • David J. Hinrichs
    • Research Service (R&D22), VA Medical Center
    • Department of Molecular Microbiology and ImmunologyOregon Health and Science University
  • Jongtae Yang
    • Department of Pharmaceutical Sciences, College of PharmacyOregon State University
  • T. Mark Zabriskie
    • Department of Pharmaceutical Sciences, College of PharmacyOregon State University
  • Martin J. Smilkstein
    • Research Service (R&D22), VA Medical Center
    • Department of ChemistryPortland State University
  • Michael K. Riscoe
    • Research Service (R&D22), VA Medical Center
    • Department of Molecular Microbiology and ImmunologyOregon Health and Science University
    • Department of ChemistryPortland State University
Original Investigation

DOI: 10.1007/s00213-014-3446-0

Cite this article as:
Janowsky, A., Eshleman, A.J., Johnson, R.A. et al. Psychopharmacology (2014) 231: 2771. doi:10.1007/s00213-014-3446-0

Abstract

Rationale

Mefloquine is used for the prevention and treatment of chloroquine-resistant malaria, but its use is associated with nightmares, hallucinations, and exacerbation of symptoms of post-traumatic stress disorder. We hypothesized that potential mechanisms of action for the adverse psychotropic effects of mefloquine resemble those of other known psychotomimetics.

Objectives

Using in vitro radioligand binding and functional assays, we examined the interaction of (+)- and (−)-mefloquine enantiomers, the non-psychotomimetic anti-malarial agent, chloroquine, and several hallucinogens and psychostimulants with recombinant human neurotransmitter receptors and transporters.

Results

Hallucinogens and mefloquine bound stereoselectively and with relatively high affinity (Ki = 0.71–341 nM) to serotonin (5-HT) 2A but not 5-HT1A or 5-HT2C receptors. Mefloquine but not chloroquine was a partial 5-HT2A agonist and a full 5-HT2C agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy as the hallucinogen dimethyltryptamine (DMT). 5-HT receptor antagonists blocked mefloquine’s effects. Mefloquine had low or no affinity for dopamine D1, D2, D3, and D4.4 receptors, or dopamine and norepinephrine transporters. However, mefloquine was a very low potency antagonist at the D3 receptor and mefloquine but not chloroquine or hallucinogens blocked [3H]5-HT uptake by the 5-HT transporter.

Conclusions

Mefloquine, but not chloroquine, shares an in vitro receptor interaction profile with some hallucinogens and this neurochemistry may be relevant to the adverse neuropsychiatric effects associated with mefloquine use by a small percentage of patients. Additionally, evaluating interactions with this panel of receptors and transporters may be useful for characterizing effects of other psychotropic drugs and for avoiding psychotomimetic effects for new pharmacotherapies, including antimalarial quinolines.

Keywords

MefloquineChloroquineQuinineMalariaLSDPsychotomimeticNeurotransmitterTransporterSerotonin receptorDopamine receptor

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2014