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Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

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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 (K i = 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.

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Acknowledgements

We thank Yuan Chou for technical expertise in the mitogenesis assays. This work was supported by a grant from the National Institute on Drug Abuse [1P50 DA018165], and NIH/VA Interagency Agreement [ADA 12013], a V.A. Merit Review [1I01BX000939-01] and the V.A. Research Career Scientist Program (AJ), and by the Bill and Melinda Gates Foundation (TMZ).

Conflict of interest

There are no conflicts of interest. The authors have full control of primary data and will allow the journal to review their data if requested.

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Authors and Affiliations

  1. Research Service (R&D22), VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA

    Aaron Janowsky, Amy J. Eshleman, Robert A. Johnson, David J. Hinrichs, Martin J. Smilkstein & Michael K. Riscoe

  2. Departments of Psychiatry and Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA

    Aaron Janowsky, Amy J. Eshleman, Robert A. Johnson & Katherine M. Wolfrum

  3. The Methamphetamine Abuse Research Center, Oregon Health and Science University, Portland, OR, 97239, USA

    Aaron Janowsky

  4. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, 97239, USA

    David J. Hinrichs & Michael K. Riscoe

  5. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, 97331, USA

    Jongtae Yang & T. Mark Zabriskie

  6. Department of Chemistry, Portland State University, Portland, OR, 97201, USA

    Martin J. Smilkstein & Michael K. Riscoe

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  1. Aaron Janowsky
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  2. Amy J. Eshleman
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  3. Robert A. Johnson
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  8. Martin J. Smilkstein
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Correspondence to Aaron Janowsky.

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Authorship contributions

Participated in research design: Janowsky, Smilkstein, Hinrichs, and Riscoe

Contributed new reagents or analytical tools: Yang, and Zabriskie

Performed experiments and conducted data analysis: Johnson, Wolfrum, Yang, and Eshleman

Wrote or contributed to the writing of the manuscript: Janowsky, Smilkstein, Riscoe, Eshleman, and Zabriskie

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Janowsky, A., Eshleman, A.J., Johnson, R.A. et al. Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro. Psychopharmacology 231, 2771–2783 (2014). https://doi.org/10.1007/s00213-014-3446-0

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