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 (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.

Potentiation of Amitriptyline Anti-Hyperalgesic-Like Action By Astroglial Connexin 43 Inhibition in Neuropathic Rats

“…Furthermore, its pharmacological profile indicates a relatively good selectivity as a Cx channel inhibitor. In particular, its affinity/potency at various serotonin (5-HT) and noradrenaline (NA) receptors and transporters mediating the anti-hyperalgesic and anti-allodynic effects of tricyclic antidepressants47 was low enough (EC 50  = 9.3 μM on 5-HT 3 receptors48; K i  > 9 μM and 3.8 μM on 5-HT 1A receptors and 5-HT 2C receptors, respectively49; EC 50  > 1.9 μM on 5-HT 2A receptors ; EC 50  > 5 μM on NA re-uptake49) to rule out any direct action of in vivo treatment at the dose of 1 mg/kg, leading to maximal mefloquine brain concentration around 0.5 μM40.…”

Autophagy Regulates Formation of Primary Cilia in Mefloquine-Treated Cells

“…However, its exact mode of action is not fully elucidated ( Toovery, 2009 ). Mefloquine binds to a number of receptors in the brain and has a high affinity to serotonin receptors ( Janowsky et al ., 2014 ). In cortical neurons, mefloquine also induces oxidative stress which is involved in many diseases, such as neurodegenerative diseases, cancer, diabetes, and ciliopathies ( Hood et al ., 2010 ; Kim et al ., 2013 ).…”

Behavioral effects of mefloquine in tail suspension and light/dark tests

“…However, as previously discussed, mefloquine’s effects on the brain are many. Greater activity could be indicative of anxiolysis, given mefloquine’s effects in fear-mediating areas of the brain (Bissiere et al 2011 ; Chung and Moore 2009 ), or it could be indicative of greater arousal due to effects on adenosine (Alisky et al 2006 ; Shepherd 1988 ), serotonin (Janowsky et al 2014 ), dopamine (Allison et al 2011 ), or effects on sleep-waking systems (Beck et al 2008 , Garcia-Rill et al 2007 ). The present study on its own, while supporting the idea of a fundamental emotional disinhibition, cannot determine whether the behavioral effects seen are indicative of anxiolytic, anti-depressive, or arousal based effects.…”

“…The mechanisms by which mefloquine could potentially create adverse effects on mood and emotional functioning are numerous. Mefloquine has also been shown to affect gap junction activity by blocking the connexin36 protein (Nevin 2012c ; Voss et al 2009 ; Juszczak and Swiergiel 2009 ; Alisky et al 2006 ), to alter dopaminergic and cholinergic activity, and calcium homeostasis (Juszczak and Swiergiel 2009 ; Alisky et al 2006 ; Nevin 2011 ; Allison et al 2011 ), to stimulate 5-HT2A and 5-HT2C receptors with similar potency and efficacy as the hallucinogen dimethyltryptamine (Janowsky et al 2014 ), to alter activity in basolateral amygdala, important to the mediation of fear and anxiety states (Chung and Moore 2009 ), to impair fear-based learning through blocking of hippocampal gap junctions (Bissiere et al 2011 ), to potentially alter sleep-waking related activity in reticular activating sites (Beck et al 2008 ; Garcia-Rill et al 2007 ), and to antagonize adenosine receptors (Alisky et al 2006 ; Shepherd 1988 ). Rodent studies have found that mefloquine administration led to changes in sleep phase activity, motor function (proprioception), lesions in brain stem, especially the nucleus gracillis (Dow et al 2006 ), and induced tonic seizures (Amabeoku and Farmer 2005 ).…”