Inhibition of neuronal Ca super(2+) influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices

• Published in: British journal of pharmacology Vol. 130; no. 4; pp. 900 - 906
• Main Authors: Fink, K, Meder, W, Dooley, D J, Goethert, M
• Format: Journal Article
• Language: English
• Published: 01-06-2000
• Subjects: gabapentin
• ISSN: 0007-1188

Cytosolic calcium ion concentrations ([Ca super(2+)] sub(i)) were measured in rat neocortical synaptosomes using fura-2, and depolarization of synaptosomal membranes was induced by K super(+) (30 mM). The release of the endogenous excitatory amino acids glutamate and aspartate was evoked by K super(+) (50 mM) and determined by HPLC. The release of [ super(3)H]-noradrenaline from rat neocortical synaptosomes or slices was evoked by K super(+) (15 and 25 mM) and measured by liquid scintillation counting. Gabapentin produced a concentration-dependent inhibition of the K super(+)-induced [Ca super(2+)] sub(i) increase in synaptosomes (IC sub(50) = 14 mu M; maximal inhibition by 36%). The inhibitory effect of gabapentin was abolished in the presence of the P/Q-type Ca super(2+) channel blocker omega -agatoxin IVA, but not by the N-type Ca super(2+) channel antagonist omega -conotoxin GVIA. Gabapentin (100 mu M) decreased the K super(+)-evoked release of endogenous aspartate and glutamate in neocortical slices by 16 and 18%, respectively. Gabapentin reduced the K super(+)-evoked [ super(3)H]-noradrenaline release in neocortical slices (IC sub(50) = 48 mu M; maximal inhibition of 46%) but not from synaptosomes. In the presence of the AMPA receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide (NBQX), gabapentin did not reduce [ super(3)H]-noradrenaline release. Gabapentin did, however, cause inhibition in the presence of the NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849). Gabapentin is concluded to reduce the depolarization-induced [Ca super(2+)] sub(i) increase in excitatory amino acid nerve terminals by inhibiting P/Q-type Ca super(2+) channels; this decreased Ca super(2+) influx subsequently attenuates K super(+)-evoked excitatory amino acid release. The latter effect leads to a reduced activation of AMPA receptors which contribute to K super(+)-evoked noradrenaline release from noradrenergic varicosities, resulting in an indirect inhibition of noradrenaline release.