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Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro Public Deposited

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https://ir.library.oregonstate.edu/concern/articles/08612q45b

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  • 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.
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  • 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
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  • 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).
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  • To the best of our knowledge, one or more authors of this paper were federal employees when contributing to this work.
  • description.provenance : Submitted by Erin Clark (erin.clark@oregonstate.edu) on 2014-10-09T17:53:17ZNo. of bitstreams: 1YangJongtaePharmacyMefloquinePsychotomimeticsShare.pdf: 1148698 bytes, checksum: c027cfd3e7acbadbcb8150fec0dba0c4 (MD5)
  • description.provenance : Made available in DSpace on 2014-10-09T17:53:42Z (GMT). No. of bitstreams: 1YangJongtaePharmacyMefloquinePsychotomimeticsShare.pdf: 1148698 bytes, checksum: c027cfd3e7acbadbcb8150fec0dba0c4 (MD5) Previous issue date: 2014-07
  • description.provenance : Approved for entry into archive by Erin Clark(erin.clark@oregonstate.edu) on 2014-10-09T17:53:42Z (GMT) No. of bitstreams: 1YangJongtaePharmacyMefloquinePsychotomimeticsShare.pdf: 1148698 bytes, checksum: c027cfd3e7acbadbcb8150fec0dba0c4 (MD5)

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