Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neurological 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 microM), 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 GABAA 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 microM. Presumptive calcium currents were inhibited by lamotrigine at 100 microM. 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.
Lees
G
G
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, UK.
Leach
M J
MJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004594:Electrophysiology; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects; D000077213:Lamotrigine; D009457:Neuroglia / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000927:Anticonvulsants; D015220:Calcium Channels; D007473:Ion Channels; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D014227:Triazines; D005680:gamma-Aminobutyric Acid; D000077213:Lamotrigine