The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex in vitro.
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 of synaptic transmitters. Neurochemical studies have shown that it can inhibit the veratrine-stimulated release of the excitatory transmitter, glutamate from cortical tissue, but that at slightly higher concentrations it also reduces the release of the inhibitory transmitter, GABA. In the present study 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 postsynaptic currents (IPSCs). Lamotrigine reduced the frequency, but not the amplitude of spontaneous EPSCs. This clearly indicated a presynaptic effect to reduce the release of glutamate. However, the same effect was observed when we tested the drug on miniature EPSCs, recorded in the presence of TTX and Cd, showing that blockade of Na-channels or Ca-channels was not a prerequisite for inhibition of glutamate release. In contrast to it's effects on EPSCs, lamotrigine increased both the frequency and amplitude of spontaneous IPSCs, suggesting that the drug was acting presynaptically to enhance GABA release. Again, similar effects were seen with miniature IPSCs recorded in TTX. These opposite effects of lamotrigine on glutamate and GABA release are similar to those we have reported previously with phenytoin, and suggest that reciprocal modulation of the background release of the major excitatory and inhibitory transmitters may be a significant factor in dampening excitability in pathologically hyperexcitable cortical networks.
Cunningham
M O
MO
Department of Physiology, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.
Jones
R S
RS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D018728:Entorhinal Cortex / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000187:drug effects* / Q000378:metabolism; D000077213:Lamotrigine; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014227:Triazines / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000378:metabolism
D000927:Anticonvulsants; D014227:Triazines; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077213:Lamotrigine