Gammahydroxybutyrate (GHB) receptor ligand effects on evoked synaptic field potentials in CA1 of the rat hippocampal slice.
GHB produced a concentration-dependent depression of evoked synaptic field potentials (EFPs) recorded extracellularly in the CA1 region of the in vitro rat hippocampal slice. The concentration/response function revealed a threshold near 1 mM, with IC50 of 10.85 mM and a Hill coefficient of 1.29. The gamma-aminobutyric acid B-receptor (GABA-B) agonist baclofen also depressed the EFP, but even maximally effective concentrations of the GABA-B antagonist 2-hydroxy-saclofen (800 microM) could not completely block the GHB-induced EFP depression. Nor was GHB-induced EFP depression blocked by the GHB receptor "antagonist" NCS-382, which does not displace GABA-B receptor ligands. However, NCS-382 produced a concentration-dependent increase in EFP slope. The threshold concentration was about 100 microM but the maximally effective concentration, and thus the IC50, could not be determined in the perfusion slice system. NCS-382 may be an inverse agonist at hippocampal GHB receptors, or else endogenous hippocampal GHB receptor ligands medicate a tonic inhibition in CA1. At concentrations sufficient to induce EFP depression GHB did not alter pH. Although isosmotic sucrose did depress CA1 EFPs it was essentially ineffective at the IC50 for GHB. Gamma-butyrolactone, a prodrug of GHB, was only 1/20th as effective as GHB. This is consistent with previous data suggesting that GBL is freely permeable (does not substantially disturb tonicity) and that brain has very little capacity to either enzymatically convert the lactone to GHB or respond to the lactone itself.
King
M A
MA
VA Medical Center, University of Florida College of Medicine, Gainesville, USA.
Thinschmidt
J S
JS
Walker
D W
DW
D000818:Animals; D004558:Electric Stimulation; D004594:Electrophysiology; D005071:Evoked Potentials / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D058786:GABA-B Receptor Agonists; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists / Q000187:drug effects* / Q000502:physiology; D018080:Receptors, GABA-B / Q000378:metabolism; D013569:Synapses / Q000502:physiology*
C039403:4-hydroxybutyric acid receptor; D058786:GABA-B Receptor Agonists; D008024:Ligands; D011956:Receptors, Cell Surface; D018080:Receptors, GABA-B