Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

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 [(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.

Fig 1

Displacement of radiolabeled agonist binding to h5-HT receptors was conducted as described in Methods. Assays were conducted with duplicate determinations, and were repeated at least three times. K_i values were derived from the Cheng-Prusoff correction and used radioligand K_d values as described in Methods. DOM, DMT, and LSD are psychotomimetic drugs with relatively high affinity for 5-HT receptors and were included for purposes of comparison. The K_i values are described in Table 2. Abbreviations: 5-HT serotonin; LSD lysergic acid diethylamide; DMT N,N-dimethyltryptamine; DOM 2,5-Dimethoxy-4-methylamphetamine; 8OH-DPAT 8-hydroxy-2-(di-n-propylamino) tetralin; DOI 2,5-dimethoxy-4-iodoamphetamine. Displacement of radiolabeled agonist binding by mefloquine and other drugs at the h5-HT_1A, h5-HT_2A, and h5-HT_2C receptors.

Fig 2

Stimulation of IP-1 formation was conducted as described in Methods. Assays were conducted with duplicate determinations and experiments were repeated at least three times. a, b: IP-1 formation is expressed as a percentage of IP-1 accumulation in response to the maximal effect of 5-HT. c. Data are expressed as nM IP1 to allow comparison between HEK wild-type (HEK-wt), HEK-h5-HT_2A and HEK-h5-HT_2C cells. The drug concentrations were 1 μM 5-HT, 100 μM (+)mefloquine and 10 nM LSD. Abbreviations: 5-HT serotonin; LSD lysergic acid diethylamide; DMT N,N-dimethyltryptamine; DOM 2,5-Dimethoxy-4-methylamphetamine; DOI 2,5-dimethoxy-4-iodoamphetamine; IP1 inositol-1-phosphate. Stimulation of h5-HT_2A and h5-HT_2C receptor-mediated inositol-1-phosphate accumulation by mefloquine and other drugs.

Fig 3

5-HT_2A and 5-HT_2C receptor antagonists inhibit (+)mefloquine, serotonin and LSD stimulated IP-1 formation. a. h5-HT_2A cells were preincubated with ketanserin for 10 min before the addition of agonists. n=3–4. b. h5-HT_2C cells were preincubated with SB 242084 for 10 min before the addition of agonists. n=3 h5-HT_2A and h5-HT_2C receptor antagonists inhibit (+)mefloquine-, serotonin- and LSDstimulated IP-1 formation.

Fig 4

Displacement of [³H]ketanserin and [¹²⁵I]DOI binding from h5-HT_2A receptors by agonists and antagonist. Binding assays were conducted as described in Methods. a, b, c, d, e: (+)Mefloquine, LSD, DOM, 5-HT and ketanserin concentration response curves, respectively. n=4–9 Displacement of radiolabeled agonist and antagonist binding by mefloquine and other drugs.

Fig 5

Mefloquine is an antagonist of quinpirole-stimulated mitogenesis in CHOp-D₃ cells. Assays were conducted with duplicate determinations. The number of independent experiments are given in Table 6. Mitogenesis activity is expressed in terms of [³H]thymidine incorporation. a, b: For agonists, the data is normalized to the maximal stimulation by quinpirole. c, d: For antagonists, the data is normalized to the stimulation by 30 nM quinpirole. Abbreviation: quin, quinpirole. Mefloquine is an antagonist of quinpirole-stimulated mitogenesis in CHOp-D₃ cells.