- 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
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
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.
- Janowsky, A., Eshleman, A. J., Johnson, R. A., Wolfrum, K. M., Hinrichs, D. J., Yang, J., ... & Riscoe, M. K. (2014). Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro. Psychopharmacology, 231(14), 2771-2783. doi:10.1007/s00213-014-3446-0
|Funding Statement (additional comments about funding)
- This work was supported by a grant from the NationalInstitute on Drug Abuse [1P50 DA018165], and NIH/VA InteragencyAgreement [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).
- To the best of our knowledge, one or more authors of this paper were federal employees when contributing to this work.
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