BINDING CHARACTERISTICS OF GAMMA-HYDROXYBUTYRIC ACID AS A WEAK BUT SELECTIVE GABA(B) RECEPTOR AGONIST

The aim of this study was to reexamine the concept that gamma-hydroxyb utyric acid (GHB) is a weak but selective agonist at gamma-aminobutyri c acid(B) (GABA(B)) receptors, using binding experiments with several radioligands. K-i values of GHB were similar (approximate to 100 mu M) in three agonist radioligand assays for GABA(B) receptors, [H-3]baclo fen (beta-para-chlorophenyl-gamma-aminobutyric acid), [H-3]CGP 27492 ( 3-aminopropyl-phosphinic acid) and [H-3]GABA, in the presence of the G ABA(A) receptor agonist isoguvacine with rat cortical, cerebellar and hippocampal membranes. In competition experiments between GHB and the GABA(B) receptor antagonist, [H-3]CGP 54626 (3-N ,4-dichlorophenyl}-et hylamino]-2-(S)-hydroxypropyl cyclo-hexylmethyl phosphinic acid), the IC50 values were significantly increased with 300 mu M of 5'-guanyl-im idodiphosphate (Gpp(NH)p), which suggested that guanine nucleotide bin ding proteins (G-proteins) modulate GHB binding on GABA(B) receptors. The inhibition by GHB of [H-3]CGP 27492 binding in cortical membranes was not altered in the presence of 0.3 or 3 mM of the two GHB dehydrog enase inhibitors, valproate and ethosuximide. Thus, GHB is not reconve rted into GABA by GHB dehydrogenase. Taken together, the results of th is study demonstrated that GHB is an endogenous weak but selective ago nist at GABA(B) receptors.