Psychopharmacology

, Volume 231, Issue 14, pp 2771–2783

Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

  • Aaron Janowsky
  • Amy J. Eshleman
  • Robert A. Johnson
  • Katherine M. Wolfrum
  • David J. Hinrichs
  • Jongtae Yang
  • T. Mark Zabriskie
  • Martin J. Smilkstein
  • Michael K. Riscoe
Original Investigation

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

Mefloquine Chloroquine Quinine Malaria LSD Psychotomimetic Neurotransmitter Transporter Serotonin receptor Dopamine receptor 

References

  1. AlKadi HO (2007) Antimalarial drug toxicity: a review. Chemotherapy 53:385–391PubMedCrossRefGoogle Scholar
  2. Amabeoku GJ, Farmer CC (2005) Gamma-aminobutyric acid and mefloquine-induced seizures in mice. Prog Neuropsychopharmacol Biol Psychiatr 29(6):917–921CrossRefGoogle Scholar
  3. Caridha D, Yourick D, Cabezas M, Wolf L, Hudson TH, Dow GS (2008) Mefloquine-induced disruption of calcium homeostasis in mammalian cells is similar to that induced by ionomycin. Antimicrob Agents Chemother 52(2):684–693PubMedCentralPubMedCrossRefGoogle Scholar
  4. Carroll FI, Blackwell JT (1974) Optical isomers of aryl-2-piperidylmethanol antimalarial agents. Preparation, optical purity, and absolute stereochemistry. J Med Chem 17(2):210–219PubMedCrossRefGoogle Scholar
  5. Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K i) and the concentration of an inhibitor which causes 50 per cent inhibition (I 50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108PubMedCrossRefGoogle Scholar
  6. Combrinck JM, Mabotha TE, Ncokazi KK, Ambele MA, Taylor D, Smith PJ, Hoppe HC, Egan TJ (2013) Insights into the role of heme in the mechanism of action of antimalarials. ACS Chem Biol 8(1):133–137PubMedCentralPubMedCrossRefGoogle Scholar
  7. Cruikshank SJ, Hopperstad M, Younger M, Connors BW, Spray DC, Srinivas M (2004) Potent block of Cx36 and Cx50 gap junction channels by mefloquine. Proc Natl Acad Sci U S A 101(33):12364–12369PubMedCentralPubMedCrossRefGoogle Scholar
  8. Dow GS, Milner E, Bathurst I, Bhonsle J, Caridha D, Gardner S, Gerena L, Kozar M, Lanteri C, Mannila A, McCalmont W, Moon J, Read KD, Norval S, Roncal N, Shackleford DM, Sousa J, Steuten J, White KL, Zeng Q, Charman SA (2011) Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice. Malar J 10:150PubMedCentralPubMedCrossRefGoogle Scholar
  9. Dzierszinski F, Coppin A, Mortuaire M, Dewailly E, Slomianny C, Ameisen JC, DeBels F, Tomavo S (2002) Ligands of the peripheral benzodiazepine receptor are potent inhibitors of Plasmodium falciparum and Toxoplasma gondii in vitro. Antimicrob Agents Chemother 46(10):3197–3207PubMedCentralPubMedCrossRefGoogle Scholar
  10. Egan C, Grinde E, Dupre A, Roth BL, Hake M, Teitler M, Herrick-Davis K (2000) Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT2A and 5-HT2C receptors. Synapse 35:144–150PubMedCrossRefGoogle Scholar
  11. Eshleman AJ, Carmolli M, Cumbay M, Martens CR, Neve KA, Janowsky A (1999) Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type. J Pharmacol Exp Ther 289(2):877–885PubMedGoogle Scholar
  12. Eshleman AJ, Wolfrum KM, Hatfield MG, Johnson RA, Murphy KV, Janowsky A (2013) Substituted methcathinones differ in transporter and receptor interactions. Biochem Pharmacol 85(12):1803–1815PubMedCentralPubMedCrossRefGoogle Scholar
  13. Gatch MB, Forster MJ, Janowsky A, Eshleman AJ (2011) Abuse liability profile of three substituted tryptamines. J Pharmacol Exp Ther 338(1):280–289PubMedCentralPubMedCrossRefGoogle Scholar
  14. Gazi L, Bobirnac I, Danzeisen M, Schüpbach E, Langenegger D, Sommer B, Hoyer D, Tricklebank M, Schoeffter P (1999) Receptor density as a factor governing the efficacy of the dopamine D4 receptor ligands, L-745,870 and U-101958 at human recombinant D4.4 receptors expressed in CHO cells. Br J Pharmacol 128(3):613–620PubMedCentralPubMedCrossRefGoogle Scholar
  15. Gillespie RJ, Adams DR, Bebbington D, Benwell K, Cliffe IA, Dawson CE, Dourish CT, Fletcher A, Gaur S, Giles PR, Jordan AM, Knight AR, Knutsen LJ, Lawrence A, Lerpiniere J, Misra A, Porter RH, Pratt RM, Shepherd R, Upton R, Ward SE, Weiss SM, Williamson DS (2008) Antagonists of the human adenosine A2A receptor: Part 1. Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives. Bioorg Med Chem Lett 18(9):2916–2919PubMedCrossRefGoogle Scholar
  16. Glimcher PW (2011) Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis. Proc Natl Acad Sci U S A 108(Suppl 3):15647–15654PubMedCentralPubMedCrossRefGoogle Scholar
  17. Halberstadt AL, Geyer MA (2011) Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology 61:364–381PubMedCentralPubMedCrossRefGoogle Scholar
  18. Haynes RK, Cheu KW, Chan HW, Wong HN, Li KY, Tang MM, Chen MJ, Guo ZF, Guo ZH, Sinniah K, Witte AB, Coghi P, Monti D (2012) Interactions between artemisinins and other antimalarial drugs in relation to the cofactor model—a unifying proposal for drug action. Chem Med Chem 7(12):2204–2226PubMedCrossRefGoogle Scholar
  19. Hood JE, Jenkins JW, Milatovic D, Rongzhu L, Aschner M (2010) Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons. Neurotoxicology 31(5):518–523PubMedCrossRefGoogle Scholar
  20. Iglesias R, Locovei S, Roque A, Alberto AP, Dahl G, Spray DC, Scemes E. (2008) P2X7 receptor-Pannexin1 complex: pharmacology and signaling. Am J Physiol Cell Physiol 295:C752–60Google Scholar
  21. Jones R, Kunsman G, Levine B, Smith M, Stahl C (1994) Mefloquine distribution in postmortem cases. Forensic Sci Int 68(1):29–32PubMedCrossRefGoogle Scholar
  22. Kanagarajadurai K, Malini M, Bhattacharya A, Panicker MM, Sowdhamini R (2009) Molecular modeling and docking studies of human 5-hydroxytryptamine 2A (5-HT2A) receptor for the identification of hotspots for ligand binding. Mol Biosyst 5(12):1877–1888PubMedCrossRefGoogle Scholar
  23. Kelly JX, Smilkstein MJ, Brun R, Wittlin S, Cooper RA, Lane KD, Janowsky A, Johnson RA, Dodean RA, Winter R, Hinrichs DJ, Riscoe MK (2009) Discovery of dual function acridones as a new antimalarial chemotype. Nature 459(7244):270–273PubMedCrossRefGoogle Scholar
  24. Kennedy K (2009) Army scales back use of anti-malaria drug. Army Times, March 24:2009Google Scholar
  25. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M (2004) Pharmacological characterisation of the agonist radioligand binding site of 5HT(2A), 5HT(2B) and 5HT(2C) receptors. Naunyn-Schmeideberg’s Arch Pharmacol 370:114–123Google Scholar
  26. MacLean D.S. (2013) Crazy Pills. The New York Times. August 7. Available at http://www.nytimes.com/2013/08/08/opinion/crazy-pills.html?_r=0
  27. Marona-Lewicka D, Nichols CD, Nichols DE (2011) An animal model of schizophrenia based on chronic LSD administration: old idea, new results. Neuropharmacology 61(3):503–512PubMedCentralPubMedCrossRefGoogle Scholar
  28. Milatovic D, Jenkins JW, Hood JE, Yu Y, Rongzhu L, Aschner M (2011) Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase. Neurotoxicology 32:578–585PubMedCrossRefGoogle Scholar
  29. Minuzzi L, Cumming P (2010) Agonist binding fraction of dopamine D2/3 receptors in rat brain: a quantitative autoradiographic study. Neurochem Int 56(6-7):747–752PubMedCrossRefGoogle Scholar
  30. Miyake N, Miyamoto S, Jarskog LF (2012) New serotonin/dopamine antagonists for the treatment of schizophrenia: are we making real progress? Clin Schizophr Relat Psychoses 6(3):122–133PubMedCrossRefGoogle Scholar
  31. Neve KA, Neve RL (1997) Molecular biology of dopamine receptors. In: Neve KA, Neve RL (eds) The dopamine receptors. Humana Press, TotowaCrossRefGoogle Scholar
  32. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181Google Scholar
  33. Nichols DE, Frescas S, Marona-Lewicka D, Kurrasch-Orbaugh DM. (2002) Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD). J Med Chem 45(19):4344–4349Google Scholar
  34. Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A (2008) The pharmacology of lysergic acid diethylamide: a review. CNS Neurosci Ther 14:295–314PubMedCrossRefGoogle Scholar
  35. Pham YT, Nosten F, Farinotti R, White NJ, Gimenez F (1999) Cerebral uptake of mefloquine enantiomers in fatal cerebral malaria. Int J Clin Pharmacol Ther 37(1):58–61PubMedGoogle Scholar
  36. Rabin RA, Regina M, Doat M, Winter JC (2002) 5-HT2A receptor-stimulated phosphoinositide hydrolysis in the stimulus effects of hallucinogens. Pharmacol Biochem Behav 72(1-2):29–37PubMedCrossRefGoogle Scholar
  37. Sarihi A, Mirnajafi-Zadeh J, Jiang B, Sohya K, Safari MS, Arami MK, Yanagawa Y, Tsumoto T (2012) Cell type-specific, presynaptic LTP of inhibitory synapses on fast-spiking GABAergic neurons in the mouse visual cortex. J Neurosci 32(28):13189–13199PubMedCrossRefGoogle Scholar
  38. Schlagenhauf P, Adamcova M, Regep L, Schaerer MT, Bansod S, Rhein HG. (2011) Use of mefloquine in children- a review of dosage, pharmacokinetics and tolerability data.  Malar J 10:292–302Google Scholar
  39. Schlagenhauf P, Johnson R, Schwartz E, Nothdurft HD, Steffen R (2009) Evaluation of mood profiles during malaria chemoprophylaxis: a randomized, double-blind, four-arm study. J Travel Med 16(1):42–45PubMedCrossRefGoogle Scholar
  40. Simpson JA, Price R, ter Kuile F, Teja-Isavatharm P, Nosten F, Chongsuphajaisiddhi T, Looareesuwan S, Aarons L, White NJ (1999) Population pharmacokinetics of mefloquine in patients with acute falciparum malaria. Clin Pharmacol Ther 66(5):472–484PubMedCrossRefGoogle Scholar
  41. Sleight AJ, Stam NJ, Mutel V, Vanderheyden PM (1996) Radiolabelling of the human 5-HT2A receptor with an agonist, a partial agonist and an antagonist: effects on apparent agonist affinities. Biochem Pharmacol 51(1):71–76PubMedCrossRefGoogle Scholar
  42. Thompson AJ, Lummis SC (2008) Antimalarial drugs inhibit human 5-HT3 and GABAA but not GABAC receptors. Br J Pharmacol 153(8):1686–1696PubMedCentralPubMedCrossRefGoogle Scholar
  43. Thompson AJ, Lochner M, Lummis SC (2007) The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors. Br J Pharmacol 151(5):666–677PubMedCentralPubMedCrossRefGoogle Scholar
  44. Thomson AM, West DC, Lodge D (1985) An N-methylaspartate receptor-mediated synapse in rat cerebral cortex: a site of action of ketamine? Nature 313(6002):479–481PubMedCrossRefGoogle Scholar
  45. Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS (1998) Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr 178:440–466PubMedGoogle Scholar
  46. Toovey S (2009) Mefloquine neurotoxicity: a literature review. Travel Med Infect Dis 7(1):2–6PubMedCrossRefGoogle Scholar
  47. Van Riemsdijk MM, Sturkenboom MC, Pepplinkhuizen L, Stricker BH (2005) Mefloquine increases the risk of serious psychiatric events during travel abroad: a nationwide case-control study in the Netherlands. J Clin Psychiatry 66(2):199–204PubMedCrossRefGoogle Scholar
  48. Wang Y, Denisova JV, Kang KS, Fontes JD, Zhu BT, Belousov AB. (2010) Neuronal gap junctions are required for NMDA receptor-mediated excitotoxicity: implications in ischemic stroke. J Neurophysiol 104(6):3551–3556.Google Scholar
  49. Weidekamm E, Rüsing G, Caplain H, Sörgel F, Crevoisier C (1998) Lack of bioequivalence of a generic mefloquine tablet with the standard product. Eur J Clin Pharmacol 54(8):615–619PubMedCrossRefGoogle Scholar
  50. Weiss SM, Benwell K, Cliffe IA, Gillespie RJ, Knight AR, Lerpiniere J, Misra A, Pratt RM, Revell D, Upton R, Dourish CT (2003) Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease. Neurology 61(11 Suppl 6):S101–S106PubMedCrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Aaron Janowsky
    • 1
    • 2
    • 3
  • Amy J. Eshleman
    • 1
    • 2
  • Robert A. Johnson
    • 1
    • 2
  • Katherine M. Wolfrum
    • 2
  • David J. Hinrichs
    • 1
    • 4
  • Jongtae Yang
    • 5
  • T. Mark Zabriskie
    • 5
  • Martin J. Smilkstein
    • 1
    • 6
  • Michael K. Riscoe
    • 1
    • 4
    • 6
  1. 1.Research Service (R&D22), VA Medical CenterPortlandUSA
  2. 2.Departments of Psychiatry and Behavioral NeuroscienceOregon Health and Science UniversityPortlandUSA
  3. 3.The Methamphetamine Abuse Research CenterOregon Health and Science UniversityPortlandUSA
  4. 4.Department of Molecular Microbiology and ImmunologyOregon Health and Science UniversityPortlandUSA
  5. 5.Department of Pharmaceutical Sciences, College of PharmacyOregon State UniversityCorvallisUSA
  6. 6.Department of ChemistryPortland State UniversityPortlandUSA

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