Mo. Cunningham et Rsg. Jones, The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro, NEUROPHARM, 39(11), 2000, pp. 2139-2146
It has been suggested that the anticonvulsant effect of lamotrigine resides
with it's ability to block voltage gated Na-channels at presynaptic sites,
thus stabilizing the presynapse, and, consequently, reducing the release o
f synaptic transmitters. Neurochemical studies have shown that it can inhib
it the veratrine-stimulated release of the excitatory transmitter, glutamat
e from cortical tissue, but that at slightly higher concentrations it also
reduces the release of the inhibitory transmitter, GABA. In the present stu
dy we examined the effect of the drug on the release of these transmitters
at synapses in the rat entorhinal cortex, using the whole-cell patch clamp
technique to record spontaneous excitatory (EPSCs) and inhibitory postsynap
tic currents (IPSCs). Lamotrigine reduced the frequency, but not the amplit
ude of spontaneous EPSCs. This clearly indicated a presynaptic effect to re
duce the release of glutamate. However, the same effect was observed when w
e tested the drug on miniature EPSCs, recorded in the presence of TTX and C
d, showing that blockade of Na-channels or Ca-channels was not a prerequisi
te for inhibition of glutamate release. In contrast to it's effects on EPSC
s, lamotrigine increased both the frequency and amplitude of spontaneous IP
SCs, suggesting that the drug was acting presynaptically to enhance GABA re
lease. Again, similar effects were seen with miniature IPSCs recorded in TT
X. These opposite effects of lamotrigine on glutamate and GABA release are
similar to those we have reported previously with phenytoin, and suggest th
at reciprocal modulation of the background release of the major excitatory
and inhibitory transmitters may be a significant factor in dampening excita
bility in pathologically hyperexcitable cortical networks. (C) 2000 Elsevie
r Science Ltd. All rights reserved.