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 cultured cortical rat neurones (7-21 days in vitro) in order to determine the effects of the anticonvulsant and glutamate release inhibitor Lamotrigine (10-100 muM), on CNS receptors and ion channels. The compound 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) currents. In the presence of tetrodotoxin, voltage-gated potassium currents and composite currents evoked by L-glutamate were not significantly modulated even at the highest dose. Unitary, fast, presumptive-sodium spikes, evoked at low frequencies, were not blocked significantly by lamotrigine. In contrast, burst firing induced by pulsed application of L-glutamate or potassium ions was markedly depressed at 10 muM. Presumptive calcium currents were inhibited by lamotrigine at 100 muM. It is proposed that the drug inhibits epileptiform burst firing preferentially by state/activity dependent interactions with voltage gated cation channels. Potential mechanisms for inhibition of glutamate release are discussed.