title: Inhibition of K(+)-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin.
abstract: 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 (omega-conotoxin MVIIA, omega-conotoxin MVIIC, omega-agatoxin TK) were assessed in vitro on K(+)-evoked (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/Q-type VSCC-targeting ligands reduced GLU release by 19-55% to implicate these VSCC in this Ca(2+)-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.
authors.affiliation: Department of Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, MI 48105, USA. david.dooley@wl.com
authors.forename: D J
authors.initials: DJ
authors.lastname: Dooley
authors.forename: C A
authors.initials: CA
authors.lastname: Mieske
authors.forename: S A
authors.initials: SA
authors.lastname: Borosky
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D060848:Agatoxins; D000588:Amines; D000818:Animals; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D018698:Glutamic Acid / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology*; D000069583:Pregabalin; D051381:Rats; D017207:Rats, Sprague-Dawley; D013111:Spider Venoms / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: D000085:Acetates; D060848:Agatoxins; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D013111:Spider Venoms; D020960:omega-Conotoxins; C083855:omega-agatoxin-Aa4b; C075851:omega-conotoxin-MVIIC; D018698:Glutamic Acid; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C078452:ziconotide; D011188:Potassium