DIFFERENTIAL-EFFECTS OF PHOSPHONIC ANALOGS OF GABA ON GABA(B) AUTORECEPTORS IN RAT NEOCORTICAL SLICES

The effects of five phosphonic derivatives of GABA on the release of [ H-3]-GABA from rat neocortical slices, preloaded with [3H]-GABA, were investigated. Phaclofen and 4-aminobutylphosphonic acid (4-ABPA) incre ased the overflow of [H-3] evoked by electrical stimulation (2 Hz) in a concentration-dependent manner, with similar potencies (phaclofen EC 50 = 0.3 mmol/l, 4-ABPA EC50 = 0.4 mmol/l). At 3 mmol/l, phaclofen inc reased the release of [H-3]-GABA by 82.6+/-8.6%, and 4-ABPA increased the release by 81.3+/-9.0%. 2-Amino-ethylphosphonic acid (2-AEPA) incr eased the overflow of [H-3] by 46.8+/-10.9% at the highest concentrati on tested (3 mmol/l). In contrast, the lower phosphonic homologue 3-am inopropylphosphonic acid (3-APPA), and 2-amino-2-(p-chlorophenyl)-ethy lphosphonic acid (2-CPEPA), a baclofen analogue, did not modify the st imulated overflow. These results suggest that phaclofen, 4-ABPA and 2- AEPA are antagonists at GABA(B) autoreceptors, the latter being the we akest antagonist, whilst neither 3-APPA nor 2-CPEPA are active at thes e receptors. Since phaclofen, 4-ABPA and 2-CPEPA are antagonists and 3 -APPA a partial agonist/antagonist on GABA(B) heteroreceptors, the lac k of effect of 3-APPA and 2-CPEPA on [H-3]-GABA release in this study suggests that GABA(B) autoreceptors may be pharmacologically distinct from the heteroreceptors.