Effects of gabapentin and pregabalin on K+-evoked 3H-GABA and 3H-glutamate release from human neocortical synaptosomes

One site of action of the anticonvulsant, analgesic, and anxiolytic drugs gabapentin and pregabalin is the α2δ-subunit of voltage-sensitive Ca2+ channels (VSCC). We therefore analyzed the effects of gabapentin and pregabalin on K+-evoked release of 3H-γ-aminobutyric acid (GABA) and 3H-glutamate from superfused human neocortical synaptosomes. These neurotransmitters are released by Ca2+-dependent exocytosis and by Ca2+-independent uptake reversal. When a GABA transport inhibitor was present throughout superfusion to isolate exocytotic conditions, gabapentin and pregabalin (100 μM each) reduced K+-evoked 3H-GABA release by 39% and 47%, respectively. These effects were antagonized by the α2δ-ligand l-isoleucine (1 μM) suggesting the α2δ-subunit of terminal VSCC to mediate the reduction of exocytosis. Both drugs had no effect on exocytotic 3H-glutamate release and also failed to modulate the release of 3H-GABA and 3H-glutamate caused by reversed uptake in the absence of external Ca2+. Thus, an inhibition of glutamate release by gabapentin and pregabalin as main anticonvulsant principle is not supported by our experiments. An anticonvulsant mode of action of both drugs may be the reduction of a proconvulsant exocytotic GABA release.