GAMMAHYDROXYBUTYRATE (GHB) RECEPTOR-LIGAND EFFECTS ON EVOKED SYNAPTICFIELD POTENTIALS IN CA1 OF THE RAT HIPPOCAMPAL SLICE

GHB produced a concentration-dependent depression of evoked synaptic f ield potentials (EFPs) recorded extracellularly in the CA1 region of t he in vitro rat hippocampal slice. The concentration/response function revealed a threshold near 1 mM, with IC50 of 10.85 mM and a Hill coef ficient of 1.29. The gamma-aminobutyric acid B-receptor (GABA-B) agoni st baclofen also depressed the EFP, but even maximally effective conce ntrations of the GABA-B antagonist 2-hydroxy-saclofen (800 mu M) could not completely block the GHB-induced EFP depression. Nor was GHB-indu ced EFP depression blocked by the GHB receptor ''antagonist'' NCS-382, which does not displace GABA-B receptor ligands. However, NCS-382 pro duced a concentration-dependent increase in EFP slope. The threshold c oncentration was about 100 mu M but the maximally effective concentrat ion, and thus the IC50, could not be determined in the perfusion slice system. NCS-382 may be an inverse agonist at hippocampal GHB receptor s, or else endogenous hippocampal GHB receptor ligands mediate a tonic inhibition in CA1. At concentrations sufficient to induce EFP depress ion GHB did not alter pH. Although isosmotic sucrose did depress CAI E FPs it was essentially ineffective at the IC50 for GHB. Gamma-butyrola ctone, a prodrug of GHB, was only 1/20th as effective as GHB. This is consistent with previous data suggesting that GEL is freely permeable (does not substantially disturb tonicity) and that brain has very litt le capacity to either enzymatically convert the lactone to GHB or resp ond to the lactone itself.