Abstract
Mefloquine, a widely used antimalarial drug, has many neuropsychiatric effects. Although the mechanisms underlying these side effects remain unclear, recent studies show that mefloquine enhances spontaneous transmitter release and inhibits cholinesterases. In this study, we examined the effect of mefloquine on GABA receptor-mediated, spontaneous inhibitory postsynaptic currents (sIPSCs) of dopaminergic neurons, mechanically dissociated from the substantia nigra pars compacta of rats aged 6 to 17 postnatal days. Mefloquine (0.1–10 μM) robustly and reversibly increased the frequency of sIPSCs with an EC50 of 1.3 μM. Mefloquine also enhanced the frequency of miniature inhibitory postsynaptic currents in the presence of tetrodotoxin but without changing their mean amplitude. This suggests that mefloquine acts presynaptically to increase GABA release. Mefloquine-induced enhancement of sIPSCs was significantly attenuated in medium containing low Ca2+ (0.5 mM) or following pretreatment with 1,2-bis (2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester (30 μM), a membrane-permeable Ca2+ chelator. In contrast, 100 μM Cd2+ did not alter the action of mefloquine. This suggests that mefloquine-induced facilitation of GABA release depends on extracellular and intraterminal Ca2+ but not on voltage-gated Ca2+ channels. Mefloquine-induced enhancement of sIPSCs was significantly attenuated in the presence of the anticholinesterase agent physostigmine or blockers of non-α7 nicotinic acetylcholine receptors. Taken together, these data suggest that mefloquine enhances GABA release through its inhibition of cholinesterase. This allows accumulation of endogenously released acetylcholine, which activates neuronal nicotinic receptors on GABAergic nerve terminals. The resultant increase of Ca2+ entry into these terminals enhances vesicular release of GABA. This action may contribute to the neurobehavioral effects of mefloquine.
Footnotes
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This publication was made possible by Grants AA-11989 from the National Institute of Alcohol Abuse and Alcoholism and AT-001182 from the National Center for Complementary and Alternative Medicine and by an award from University of Medicine and Dentistry of New Jersey Foundation (to J.H.Y.) as well as Grant NS045979 from the National Institute of Neurological Disorders and Stroke and an award from the Kirby Foundation (to J.J.M.).
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doi:10.1124/jpet.106.101923.
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ABBREVIATIONS: mEPPS, miniature endplate potentials; BAPTA-AM, 1,2-bis (2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester; DA, dopaminergic; SNc, substantia nigra pars compacta; APV, dl-2-amino-5-phosphono-valeric acid; DNQX, 6,7-dinitroquinoxaline-2, 3-dione; TTX, tetrodotoxin; QP, quinpirole hydrochloride; MEC, mecamylamine hydrochloride; DHβE, dihydro-β-erythroidine hydrobromide; α-BgTX, α-bungarotoxin; IPSC, inhibitory postsynaptic current; sIPSC, spontaneous IPSC; K-S, Kolmogorov-Smirnov; mIPSC, miniature IPSC; VGCC, voltage-gated calcium channel; PHY, physostigmine; nAChR, nicotinic acetylcholine receptor; AChE, cholinesterase.
- Received January 26, 2006.
- Accepted February 22, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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