Received for publication January 27, 2006.
Revised February 22, 2006.
Accepted for publication February 22, 2006.

Mefloquine enhances nigral -aminobutyric acid release via inhibition of cholinesterase

Abstract

Mefloquine, a widely used antimalarial drug, has many neuropsychiatric effects. While 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 -aminobutyric acid (GABA) receptor mediated, spontaneous inhibitory postsynaptic currents (sIPSCs) of dopaminergic neurons, mechanically dissociated from the substantia nigra pars compacta of rats aged 6-17 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 IPSCs 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 BAPTA-AM (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-7 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.

Key words: Acetylcholinesterase, Dopamine, Electrophysiology, Inhibitory postsynaptic currents, Substantia nigra, Synaptic transmission

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