GABA(B) receptors as potential targets for drugs able to prevent excessive excitatory amino acid transmission in the spinal cord.

The effects of GABA(B) receptor activation on the Ca2+-dependent depolarization-induced overflow of endogenous glutamic acid and gamma-aminobutyric acid (GABA) was studied in rat spinal cord nerve terminals exposed in superfusion to 15 mM KCl. The GABA(B) receptor agonist (-)-baclofen inhibited the K+-evoked overflow of glutamate (EC50=0.098 microM) but was almost inactive against that of GABA. The overflow of both transmitters could be quite similarly inhibited by two other GABA(B) receptor agonists, 3-APPA (3-aminopropylphosphonous acid; EC50=0.087 and 0.050 microM in the case of GABA and glutamate, respectively) and CGP 44532 (3-amino-2(S)-hydroxypropyl)methylphosphinic acid; EC50=0.81 and 0.50 microM). The GABA(B) receptor antagonist CGP 35348 [3-amino-propyl(diethoxymethyl)phosphinic acid] blocked the effect of 3-APPA (1 microM) at the autoreceptors (IC50 approximately = 1 microM), but not at the heteroreceptors. In contrast, the effects of 3-APPA at both autoreceptors and heteroreceptors could be similarly prevented by another GABA(B) receptor antagonist, CGP 52432 [3-[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl) phosphinic acid (IC50 approximately = 10 microM). The data suggest that, in the spinal cord, GABA(B) autoreceptors on GABA-releasing terminals differ pharmacologically from GABA(B) heteroreceptors on glutamatergic terminals. Selective GABA(B) receptor ligands may be helpful for conditions characterized by excessive glutamatergic transmission in the spinal cord.