GABAB receptors as potential targets for drugs able to prevent excessive excitatory amino acid transmission in the spinal cord

The effects of GABA, 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, receptor agonist (-)-baclofen inhibited the K+-evoked overflow of glutamate (EC50 = 0.098 mu M) 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 mu M in the case of GABA and glutamate, respectively) and CGP 44532 (3-amino-2(S)-hydroxypropyl)methylphosphinic acid (EC50 = 0.81 and 0.50 mu M). The GABA(B) receptor antagonist CGP 35348 [3-amino-propyl(diethoxymethyl)phosphinic acid] blocked the effect of 3-APPA (1 mu M) at the autoreceptors (IC50 = 1 mu M), but not at the heteroreceptors. In contrast, the effects of 3-APPA at both autoreceptors and heteroreceptors could be similarly prevented by another GABA, receptor antagonist, CGP 52432 [3-[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl) phosphinic acid (IC50 similar or equal to 10 mu M). The data suggest that, in the spinal cord, GABA, autoreceptors on GABA-releasing terminals differ pharmacologically from GABA, heteroreceptors on glutamatergic terminals. Selective GABA, receptor ligands may be helpful for conditions characterized by excessive glutamatergic transmission in the spinal cord. (C) 1998 Elsevier Science B.V. All rights reserved.