Inhibition of neuronal Ca2+ influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices

Cytosolic calcium ion concentrations ([Ca2+](i)) were measured in rat neoco rtical synaptosomes using fura-2, and depolarization of synaptosomal membra nes was induced by K+ (30 mM). The release of the endogenous excitatory. am ino acids glutamate and aspartate was evoked by K+ (50 mM) and determined b y HPLC. The release of [H-3]-noradernaline from rat neocortical synaptosome s or slices was evoked by K+ (15 and 25 mM) and measured by liquid scintill ation counting. 2 Gabapentin produced a concentration-dependent inhibition of the K+-induce d[Ca2+](i) increase in synaptosomes (IC50 = 14 mu M; maximal inhibition by 36%). The inhibitory effect of gabapentin was abolished in the presence of the P/Q-type Ca2+ channel blocker omega-agatoxin IVA, but not by the N-type Ca2+ channel antagonist omega-conotoxin GVIA. 3 Gabapentin (100 mu M) decreased the K+-evoked release of endogenous aspar tate and glutamate in neocortical slices by 16 and 18% respectively. 4 Gabapentin reduced the K+-evoked [H-3]-noradrenaline release in neocortic al slices (IC50 = 48 mu M; maximal inhibition of 46%) but not from synaptos omes. 5 In the presence of the AMPA receptor antagonists 6-cyano-7-nitroquinoxali ne-2,3-dione (CNQX) and 2.3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline- 7-sulphonamide (NBQX), gabapentin did not reduce [H-3]-noradrenaline releas e. Gabapentin did, however, cause inhibition in the presence of the NMDA re ceptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849). 6 Gabapentin is concluded to reduce the depolarizatian-induced [Ca2+](i) in crease in excitatory amino acid nerve terminals by inhibiting P/Q-type Ca2 channels; this decreased Ca2+ influx subsequently attenuates K+-evoked exc itatory amino acid release. The latter effect leads to a reduced activation of AMPA receptors which contribute to K+-evoked noradrenaline release from noradrenergic varicosities, resulting in an indirect inhibition of noradre naline release.