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 α2δ 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 μM, corresponding to relatively high preclinical/clinical plasma levels) on the release of neurotransmitters in human neocortical slices. These slices were prelabeled with 3H-dopamine (3H-DA), 3H-choline (to release 3H-acetylcholine (3H-ACh)), 3H-noradrenaline (3H-NA), and 3H-serotonin (3H-5-HT), and stimulated twice in superfusion experiments by elevation of extracellular K+ in the presence and absence of GBP and PGB. The α2δ ligands produced significant inhibitions of K+-evoked 3H-ACh, 3H-NA, and 3H-5-HT release between 22% and 56% without affecting 3H-DA release. Neither drug reduced 3H-NA release in the presence of l-isoleucine, a putative α2δ 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 α2δ 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.