Differential modulation of K+-evoked 3H-neurotransmitter release from human neocortex by gabapentin and pregabalin

Anticonvulsant, analgesic, and anxiolytic effects have been observed both in preclinical and clinical studies with gabapentin (GBP) and pregabalin (PGB). These drugs appear to act by binding to the alpha(2)delta subunit of voltage-sensitive Ca2+ channels (VSCC), resulting in the inhibition of neurotransmitter release. In this study, we examined the effects of GBP and PGB (mostly 100 mu M, corresponding to relatively high preclinical/clinical plasma levels) on the release of neurotransmitters in human neocortical slices. These slices were prelabeled with H-3-dopamine (H-3-DA), H-3-choline (to release H-3-acetylcholine (H-3-ACh)), H-3-noradrenaline (H-3-NA), and H-3-serotonin (H-3-5-HT), and stimulated twice in superfusion experiments by elevation of extracellular K+ in the presence and absence of GBP and PGB. The alpha(2)delta ligands produced significant inhibitions of K+-evoked H-3-ACh, H-3-NA, and H-3-5-HT release between 22% and 56% without affecting H-3-DA release. Neither drug reduced H-3-NA release in the presence of L-isoleucine, a putative alpha(2)delta antagonist. Interestingly, this antagonism did not occur using the enantiomer, D-isoleucine. These results suggest that GBP and PGB are not general inhibitors of VSCC and neurotransmitter release. Such alpha(2)delta ligands appear to be selective modulators of the release of certain, but not all, neurotransmitters. This differential modulation of neurotransmission presumably contributes to their clinical profile.