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 [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 abecarnil 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 gamma-aminobutyric acid type A (GABAA) 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.
Department of Experimental Biology Bernado Loddo, University of Cagliari, Italy.
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Serra
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Ghiani
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Motzo
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Porceddu
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Biggio
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines / Q000494:pharmacology*; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate; C062769:abecarnil