Gabapentin activates presynaptic GABAB heteroreceptors in rat cortical slices.
In electrically stimulated rat neocortical brain slices preloaded with [3H]gamma-aminobutyric acid (GABA) or [3H]glutamic acid, the pharmacological actions of 1-(aminomethyl)-cyclohexaneacetic acid (gabapentin, Gp) were compared with the GABAB receptor agonists baclofen (Bac) and (3-amino-2-(S)-hydroxypropyl)-methylphosphinic acid (CGP 44532). Gabapentin, baclofen and CGP 44532 all reduced the electrically stimulated release of [3H]glutamic acid (IC50=20 microM, 0.8 microM and 2 microM, respectively). These effects were sensitive to the GABAB receptor antagonists (+)-(S)-5,5 dimethylmorpholinyl-2-acetic acid (Sch 50911) or N-3-[[1-(S)-(3,4-dichlorophenyl)ethyl]amino]-2-(S)-hydroxypropyl-P-(cyclo-hexylmethyl)-phosphinic acid (CGP 54626). By contrast, gabapentin was without effect on the release of [3H]GABA, whilst baclofen (IC50=8 microM) and CGP 44532 (IC50=1 microM) inhibited [3H]GABA release. It is concluded that gabapentin selectively activates presynaptic GABAB heteroreceptors, but not GABAB autoreceptors, and may be a useful ligand to discriminate between presynaptic GABAB receptor subtypes.
Parker
David A S
DA
Dental School, The University of Adelaide, Adelaide, South Australia 5005, Australia.
Ong
Jennifer
J
Marino
Victor
V
Kerr
David I B
DI
D000588:Amines / Q000494:pharmacology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D000077206:Gabapentin; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology*
C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D009025:Morpholines; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; D017661:Receptors, Presynaptic; D014316:Tritium; C107353:CGP 54626; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D001418:Baclofen