BENZODIAZEPINE AND BARBITURATE LIGANDS MODULATE RESPONSES OF CULTUREDHIPPOCAMPAL-NEURONS TO THE GABA(A) RECEPTOR PARTIAL AGONIST, 4-PIOL

We have previously characterized 5-(4-piperidyl)isoxazol-3-ol (4-PIOL) as a non-desensitizing partial agonist at GABA(A) receptors and shown that the responses are mediated by short-duration channel openings co nsonant with single-ligand gated openings of the Cl- channels. We pres ently investigate whether responses of cultured rat hippocampal neuron es to 4-PIOL are modulated by benzodiazepine (BDZ) and barbiturate rec eptor ligands. Whole-cell patch-clamp recordings of maximal responses to 1 mM 4-PIOL were comparable in size to responses evoked by 10 mu M of the full GABA(A) agonist, isoguvacine. The BDZ receptor inverse ago nist, DMCM (1 mu M) reduced responses to isoguvacine (to 65.7 +/- 11.0 %) and 4-PIOL (to 69.3 +/- 3.5%) to a similar extent. The BDZ agonist, midazolam (0.1 mu M) potentiated responses to both agonists, and resu lted in responses with an early peak with later fading. Potentiation o f the peak response to 4-PIOL (to 163 +/- 14%) was significantly less than for isoguvacine (215 +/- 11%). Pentobarbital (50 mu M) caused a v ery marked, but variable, potentiation of the peak response to 4-PIOL (to 484 +/- 93%), which was significantly greater than the potentiatio n of the peak response to isoguvacine (to 304 +/- 46%), and induced fa ding. This suggests that a relatively larger number of the 4-PIOL-indu ced channel openings can be transformed to longer duration openings by pentobarbital. In conclusion, responses to 4-PIOL and isoguvacine are modulated by BDZ and barbiturate ligands in a qualitatively similar m anner, but with a number of quantitative differences which cannot be r eadily explained by the kinetic model of Macdonald and Twyman (1992). Investigation of these responses at the single-channel level could pro vide further insight into the operation of the GABA(A) receptor-ionoph ore complex. Copyright (C) 1996 Elsevier Science Ltd