Long-term treatment with abecarnil fails to induce tolerance in mice

Abstract

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 [ 35S]TBPS ( t-butylbicyclophosphorothionate) binding were compared to those of diazepam (1 mg/kg i.p.) in mice. A challenge dose (0.1 mg/kg) of abrecarnil given 12 h after the last administration of the treatment protocol markedly inhibited 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 [ 35S]TBPS binding to unwashed cerebral cortical membranes from mice treated chronically with abecarnil (−28%) or vehicle (−30%). In contrast, a challenge dose (1 mg/kg) of diazepam failed to affect motor behaviour and [ 35S]TBPS binding in mice chronically exposed to diazepam; in animals chronically treated with vehicle, diazepam markedly inhibited both exploratory behaviour (−55%) and [ 35S]TBPS binding (−21%). These results indicate that long-term treatment with abecarnil failed to induce tolerance to the effect of this drug on γ-aminobutyric acid type A (GABA A) receptor function. Accordingly, [ 35S]TBPS binding was increased (+15–26%) 12 and 48 h after discontinuation of long-term diazepam administration while no such increase in [ 35S]TBPS binding was observed for mice chronically treated with abecarnil. Moreover, whereas a significant decrease (−15%) in [ 35S]TBPS binding was observed 96 h after discontinuation of long-term diazepam treatment, chronic treatment with abecarnil did not modify this parameter. Together, these data indicate that long-term treatment with a pharmacologically effective dose of abecarnil did not induce tolerance or the discontinuation syndrome in mice.