Mefloquine enhances nigral gamma-aminobutyric acid release via inhibition of cholinesterase.
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 microM) robustly and reversibly increased the frequency of sIPSCs with an EC50 of 1.3 microM. 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 microM), a membrane-permeable Ca2+ chelator. In contrast, 100 microM 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-alpha7 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.
Zhou
Chunyi
C
Department of Anesthesiology, New Jersey Medical School (UMDNJ), 185 S. Orange Ave., Newark, NJ 07103-2714, USA.
Xiao
Cheng
C
McArdle
Joseph J
JJ
Ye
Jiang Hong
JH
D000818:Animals; D000831:Animals, Newborn; D000962:Antimalarials / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D015767:Mefloquine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000962:Antimalarials; D002800:Cholinesterase Inhibitors; D005680:gamma-Aminobutyric Acid; D002802:Cholinesterases; D002118:Calcium; D015767:Mefloquine; D004298:Dopamine