RT Journal Article
SR Electronic
T1 Mefloquine Enhances Nigral γ-Aminobutyric Acid Release via Inhibition of Cholinesterase
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1155
OP 1160
DO 10.1124/jpet.106.101923
VO 317
IS 3
A1 Chunyi Zhou
A1 Cheng Xiao
A1 Joseph J. McArdle
A1 Jiang Hong Ye
YR 2006
UL http://jpet.aspetjournals.org/content/317/3/1155.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics