Differential effects of phosphonic analogues of GABA on GABA(B) autoreceptors in rat neocortical slices.
The effects of five phosphonic derivatives of GABA on the release of [3H]-GABA from rat neocortical slices, preloaded with [3H]-GABA, were investigated. Phaclofen and 4-aminobutylphosphonic acid (4-ABPA) increased the overflow of [3H] evoked by electrical stimulation (2 Hz) in a concentration-dependent manner, with similar potencies (phaclofen EC50=0.3 mmol/l, 4-ABPA EC50=0.4 mmol/l). At 3 mmol/l, phaclofen increased the release of [3H]-GABA by 82.6+/-8.6%, and 4-ABPA increased the release by 81.3+/-9.0%. 2-Amino-ethylphosphonic acid (2-AEPA) increased the overflow of [3H] by 46.8+/-10.9% at the highest concentration tested (3 mmol/l). In contrast, the lower phosphonic homologue 3-aminopropylphosphonic acid (3-APPA), and 2-amino-2-(p-chlorophenyl)-ethylphosphonic acid (2-CPEPA), a baclofen analogue, did not modify the stimulated overflow. These results suggest that phaclofen, 4-ABPA and 2-AEPA are antagonists at GABA(B) autoreceptors, the latter being the weakest antagonist, whilst neither 3-APPA nor 2-CPEPA are active at these receptors. Since phaclofen, 4-ABPA and 2-CPEPA are antagonists and 3-APPA a partial agonist/antagonist on GABA(B) heteroreceptors, the lack of effect of 3-APPA and 2-CPEPA on [3H]-GABA release in this study suggests that GABA(B) autoreceptors may be pharmacologically distinct from the heteroreceptors.
Ong
J
J
Department of Anaesthesia and Intensive Care, The University of Adelaide, South Australia.
Marino
V
V
Parker
D A
DA
Kerr
D I
DI
D000818:Animals; D002082:Butylamines / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
C101603:2-carboxy-4-(1-phenylethen-1-yl)pyrrolidine-3-acetic acid; D002082:Butylamines; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D011437:Propylamines; D018080:Receptors, GABA-B; C079360:4-aminobutylphosphonic acid; D005680:gamma-Aminobutyric Acid; D007608:Kainic Acid; C011649:3-aminopropylphosphonic acid