LONG-TERM TREATMENT WITH ABECARNIL FAILS TO INDUCE TOLERANCE IN MICE

The effects of long-term treatment (3 times a day for 4 weeks) with a pharmacologically active dose (0.1 mg/kg i.p.) of the novel anxiolytic , abecarnil, on exploratory behaviour and [S-35]TBPS (t-butylbicycloph osphorothionate) binding were compared to those of diazepam (1 mg/kg i .p.) in mice. A challenge dose (0.1 mg/kg) of abecarnil given 12 h aft er the last administration of the treatment protocol markedly inhibite d exploratory behaviour in animals treated chronically with abecarnil (-62%) or vehicle (-87%). Consistent with this behavioural effect, the same challenge dose of abecarnil significantly reduced [S-35]TBPS bin ding to unwashed cerebral cortical membranes from mice treated chronic ally with abecarnil (-28%) or vehicle (-30%). In contrast, a challenge dose (1 mg/kg) of diazepam failed to affect motor behaviour and [S-35 ]TBPS binding in mice chronically exposed to diazepam; in animals chro nically treated with vehicle, diazepam markedly inhibited both explora tory behaviour (-55%) and [S-35]TBPS binding (-21%). These results ind icate that long-term treatment with abecarnil failed to induce toleran ce to the effect of this drug on gamma-aminobutyric acid type A (GABA( A)) receptor function. Accordingly, [S-35]TBPS binding was increased ( +15-26%) 12 and 48 h after discontinuation of long-term diazepam admin istration while no such increase in [S-35]TBPS binding was observed fo r mice chronically treated with abecarnil. Moreover, whereas a signifi cant decrease (-15%) in [S-35]TBPS binding was observed 96 h after dis continuation of long-term diazepam treatment, chronic treatment with a becarnil did not modify this parameter. Together, these data indicate that long-term treatment with a pharmacologically effective dose of ab ecarnil did not induce tolerance or the discontinuation syndrome in mi ce.