THE EFFECT OF CYCLOPYRROLONES ON GABA(A) RECEPTOR FUNCTION IS DIFFERENT FROM THAT OF BENZODIAZEPINES

The effects of the cyclopyrrolones zopiclone and suriclone on the func tion of the central gamma-aminobutyric acid type A (GABA(A)) receptor complex in mouse brain were evaluated both in vitro and in vivo. Added in vitro to mouse cerebral cortical membranes, these compounds potent ly inhibited [H-3]flumazenil binding with IC50 (50% inhibitory concent ration) values of 35.8 nM (zopiclone) and 1.1 nM (suriclone). Similar results were obtained with cerebellar membranes, indicating that these drugs do not discriminate between putative type I and type II benzodi azepine receptors. The interaction of cyclopyrrolones with recognition sites present at the level of the GABA receptor complex appears to be competitive, because zopiclone decreased the affinity of the receptor s for [H-3]flumazenil without affecting the maximal number of binding sites. Moreover, zopiclone and suriclone did not affect the rate of di ssociation of [H-3]flumazenil from benzodiazepine receptors. The in vi tro efficacy of zopiclone appeared different from that of suriclone an d the benzodiazepines diazepam and flunitrazepam. Thus, zopiclone fail ed to affect muscimol-stimulated Cl-36(-) uptake and only slightly inh ibited t-[S-35]butylbicyclophosphorothionate ([S-35]TBPS) binding. In contrast, like diazepam and flunitrazepam, suriclone increased muscimo l-stimulated Cl-36(-) uptake and markedly inhibited [S-35]TBPS binding . On the other hand, suriclone, like zopiclone, did not modify [H-3]mu scimol binding to mouse cerebral cortical membranes. Moreover, zopiclo ne antagonized the reduction in [S-35]TBPS binding elicited by the ben zodiazepine receptor full agonist diazepam. Consistent with its low ef ficacy in vitro, oral administration of zopiclone (2.5 to 100 mg/kg, p .o.) in mice failed to modify [S-35]TBPS binding subsequently measured in cerebral cortical membranes ''ex vivo''. In contrast, suriclone (1 0 to 20 mg/kg, p.o.), like diazepam, decreased [S-35]TBPS binding meas ured ex vivo. Moreover, both zopiclone (50 to 100 mg/kg, p.o.) and sur iclone (1 to 10 mg/kg, p.o.) abolished the increase in [S-35]TBPS bind ing induced by isoniazid (200 mg/kg, s.c.). These results suggest that suriclone may enhance GABAergic transmission with an efficacy similar to that of diazepam. In contrast, the low efficacy of zopiclone both in vitro and in vivo suggests that this drug may act as a partial agon ist at benzodiazepine receptors.