In vitro activity: Lamotrigine stabilises presynaptic neuronal membranes by blockade of voltage-dependent sodium channels, thus preventing the release of excitatory neurotransmitters, particularly glutamate and aspartate. In rat cerebral cortex tissue incubated with veratrine 10 mg/L, lamotrigine is twice as potent in inhibiting the release of glutamate and aspartate (ED 50 = 5.38 mg/L for each) than the release of GABA (ED50 = 11.2 mg/L), and is much less potent in inhibiting acetylcholine release (ED50 = 25.6 mg/L) when cortical slices is exposed to veratrine 75 mg/L. Basal glutamate release is unaffected. Lamotrigine inhibits high-frequency sustained repetitive firing of sodium-dependent action potentials, indicating a direct effect on voltage-activated sodium channels. Lamotrigine does not induce PCP-like central nervous system (CNS) effects, does not act by direct inhibition at the NMDA receptor, and would be expected to be devoid of the undesirable effects associated with NMDA blockade.

Drugs. 1993 Jul;46(1):152-76; Epilepsia. 1986 Sep-Oct;27(5):483-9.