gamma-Hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors

gamma-Hydroxybutyrate (GHB) is a neuromodulator with high affinity binding sites in the mammalian brain. However, the receptor for GHB has not yet bee n identified. There are indications that GHB and gamma-aminobutyric acid (G ABA) mediate their effects via the same receptor. We tested this hypothesis using GABA(B)/R1/R2 receptors co-expressed with Kir3 channels in Xenopus o ocytes; GHB activated these receptors with an EC50 of approximately 5 mM an d a maximal stimulation of 69% when compared to the GABA(B) receptor agonis t L-baclofen. GHB and L-baclofen did not amplify each others effect nor did they stimulate the GABA(B) receptor in a linearly additive manner. CGP5462 6A, 2-OH saclofen and CGP35348, three competitive GABA, receptor antagonist s, inhibited the GHB induced response completely. A concentration of 30 mM GHB displaced [I-125]CGP64213 binding at GABA(B)R1 expressed in COS cells b y 21%. These results indicate that GHB is a weak partial agonist at the GAB A binding site of GABA(B)R1/R2. (C) 1999 Elsevier Science Ltd. All rights r eserved.