Failure of long-term administration of zopiclone and zolpidem to induce tolerance in mice

The ability of a challenge dose of the cyclopyrrolone zopiclone to antagonize both the convulsions and the increase in t-[S-35]butylbicyclophosphorothionate ([S-35]TBPS) binding to the gamma-aminobutyric acid type A (GABA(A)) receptor elicited by isoniazid, an inhibitor of central GABAergic function, was evaluated in mice subjected to long-term treatment (20 mg/kg, i.p.; three times daily for 30 days) with the drug. The effects of zopiclone were compared with those of the imidazopyridine zolpidem and the benzodiazepine flunitrazepam. The challenge dose of zopiclone (10 and 100 mg/kg, i.p., respectively), administered 36 h after the last injection of the chronic treatment protocol, reduced both isoniazid-induced convulsions and the isoniazid-induced increase in [S-35]TBPS binding to the same marked extent as in control mice. Similar results were obtained in mice chronically exposed to zolpidem (15 mg/kg), i.p., whereas mice subjected to long-term treatment with flunitrazepam (I mg/kg, i.p.) became tolerant to this drug. These results indicate that long-term treatment with zopiclone or zolpidem failed to induce tolerance to the effects of these drugs on GABA(A) receptor function. Consistent with these observations, [S-35]TBPS binding was increased (+18 to 28%) 12 and 48 h after, and decreased (-15%) 96 h after, discontinuation of long-term flunitrazepam administration. In contrast, discontinuation of chronic treatment with zopiclone or zolpidem failed to modify this parameter. These data indicate that long-term treatment with the hypnotic zopiclone did not induce discontinuation syndrome in mice.