Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro.
BACKGROUND
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.


OBJECTIVE
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 [(3)H]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.
Research Service (R&D22), VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA, janowsky@ohsu.edu.
Aaron
A
Janowsky
Amy J
AJ
Eshleman
Robert A
RA
Johnson
Katherine M
KM
Wolfrum
David J
DJ
Hinrichs
Jongtae
J
Yang
T Mark
TM
Zabriskie
Martin J
MJ
Smilkstein
Michael K
MK
Riscoe
D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006213:Hallucinogens / Q000494:pharmacology*; D006801:Humans; D015767:Mefloquine / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013237:Stereoisomerism
D000962:Antimalarials; D000697:Central Nervous System Stimulants; D006213:Hallucinogens; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D002738:Chloroquine; D015767:Mefloquine