STUDIES ON THE MECHANISM OF ACTION OF THE NOVEL ANTICONVULSANT LAMOTRIGINE (LAMICTAL) USING PRIMARY NEUROGLIAL CULTURES FROM RAT CORTEX

Whole cell and perforated patch clamp experiments were conducted on cu ltured cortical rat neurones (7-21 days in vitro) in order to determin e the effects of the anticonvulsant and glutamate release inhibitor La motrigine (10-100 muM), on CNS receptors and ion channels. The compoun d inhibited, indiscriminately, both excitatory and inhibitory synaptic events which occurred spontaneously in cultured neural circuits. The drug did not mimic diazepam as a positive modulator of GABA(A) current s. In the presence of tetrodotoxin, voltage-gated potassium currents a nd composite currents evoked by L-glutamate were not significantly mod ulated even at the highest dose. Unitary, fast, presumptive-sodium spi kes, evoked at low frequencies, were not blocked significantly by lamo trigine. In contrast, burst firing induced by pulsed application of L- glutamate or potassium ions was markedly depressed at 10 muM. Presumpt ive calcium currents were inhibited by lamotrigine at 100 muM. It is p roposed that the drug inhibits epileptiform burst firing preferentiall y by state/activity dependent interactions with voltage gated cation c hannels. Potential mechanisms for inhibition of glutamate release are discussed.