Presynaptic inhibition of excitatory neurotransmission by lamotrigine in the rat amygdalar neurons.
Lamotrigine (LAG) is a new antiepileptic drug which is licensed as adjunctive therapy for partial and secondary generalized seizures. In the present study, the mechanisms responsible for its antiepileptic effect were studied in rat amygdaloid slices using intracellular recording and whole-cell patch clamp techniques. Bath application of LAG (50 microM) reversibly suppressed the excitatory postsynaptic potentials (EPSPs) and currents (EPSCs) evoked by stimulating ventral endopyriform nucleus. Synaptic response mediated by the N-methyl-D-aspartate (NMDA) receptor (EPSPNMDA) was isolated pharmacologically by application of a solution containing non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX,10 microM) and gamma-aminobutyric acidA receptor antagonist bicuculline (20 microM). LAG produced a parallel inhibition of EPSPNMDA. Postsynaptic depolarization induced by alpha-amino-5-methyl-4-isoxazole propionate (AMPA) was not altered by LAG. In addition, LAG increased the ratio of the second pulse response to the first pulse response (P2/P1), which is consistent with a presynaptic mode of action. The L-type Ca+2 channel blocker nifedipine (20 microM) had no effect on LAG-induced presynaptic inhibition. However, the depressant effect of LAG was markedly reduced in slices pretreated with N-type Ca+2 channel blocker omega-conotoxin-GVIA (omega-CgTX-GVIA, 1 microM) or a broad spectrum Ca+2 channel blocker omega-conotoxin-MVIIC (omega-CgTX-MVIIC, 1 microM). It is concluded that a reduction in omega-CgTX-GVIA-sensitive Ca+2 currents largely contributes to LAG-induced presynaptic inhibition.
Wang
S J
SJ
Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan City, Taiwan, Republic of China.
Huang
C C
CC
Hsu
K S
KS
Tsai
J J
JJ
Gean
P W
PW
D000679:Amygdala / Q000166:cytology / Q000187:drug effects*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004594:Electrophysiology; D018846:Excitatory Amino Acids / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D000077213:Lamotrigine; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017661:Receptors, Presynaptic / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D014227:Triazines / Q000494:pharmacology*
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D018846:Excitatory Amino Acids; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D017661:Receptors, Presynaptic; D014227:Triazines; D000077213:Lamotrigine