Inhibition of K+-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin

Gabapentin (Neurontin(R)) has preclinical and clinical efficacy as an anticonvulsant, antihyperalgesic, anxiolytic, and neuroprotective drug. Since L-glutamic acid (GLU) is involved in various CNS (central nervous system) disorders, gabapentin may attenuate the release of this neurotransmitter possibly by interacting with the auxiliary alpha(2)delta subunit of voltage-sensitive calcium channels (VSCC). The effects of gabapentin, pregabalin (S-(+)3-isobutylgaba) and its enantiomer R-(-)3-isobutylgaba, and N- and P/Q-type VSCC-targeting peptide ligands (w-conotoxin MVIIA, w-conotoxin MVIIC, w-agatoxin TK) were assessed in vitro on K+-cevoked (endogenous) GLU release from rat neocortical and hippocampal slices. Gabapentin and pregabalin decreased GLU release by 11-26% with R-(-)-3-isobutylgaba being less effective than pregabalin. The reference N- and P/O-type VSCC-targeting ligands reduced GLU release by 19-55% to implicate these VSCC in this Ca2+-dependent process. The inhibitory effect of gabapentin and related compounds on GLU release may reflect a subtle modulation of VSCC function which normalizes pathological changes in neurotransmitter release. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.