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

The effects of GABA, receptor activation on the Ca2+-dependent depolarizati on-induced overflow of endogenous glutamic acid and gamma-aminobutyric acid (GABA) was studied in rat spinal cord nerve terminals exposed in superfusi on to 15 mM KCl. The GABA, receptor agonist (-)-baclofen inhibited the K+-e voked overflow of glutamate (EC50 = 0.098 mu M) but was almost inactive aga inst that of GABA. The overflow of both transmitters could be quite similar ly inhibited by two other GABA(B) receptor agonists, 3-APPA (3-aminopropylp hosphonous acid; EC50 = 0.087 and 0.050 mu M in the case of GABA and glutam ate, respectively) and CGP 44532 (3-amino-2(S)-hydroxypropyl)methylphosphin ic acid (EC50 = 0.81 and 0.50 mu M). The GABA(B) receptor antagonist CGP 35 348 [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 heteror eceptors. In contrast, the effects of 3-APPA at both autoreceptors and hete roreceptors could be similarly prevented by another GABA, receptor antagoni st, 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. S elective GABA, receptor ligands may be helpful for conditions characterized by excessive glutamatergic transmission in the spinal cord. (C) 1998 Elsev ier Science B.V. All rights reserved.