Alpidem is a new
anxiolytic of
imidazopyridine structure which has a high affinity for the omega 1 (BZ1) modulatory site of the GABAA receptor. The present study investigated whether tolerance and physical dependence develop after repeated treatment with
alpidem, as is observed with
benzodiazepines. Mice were given
alpidem (100 mg/kg, p.o.) or
diazepam (5 mg/kg, p.o.) twice daily for 10 consecutive days. Tolerance was assessed by measuring antagonism of
pentylenetetrazole- and
isoniazid-induced convulsions and
bicuculline-provoked mortality, following repeated
drug treatment. Decreases in the latency to
isoniazid-induced convulsions and in the minimal
convulsant dose of
pentylenetetrazole were taken as an index of physical dependence and were evaluated at different times (3, 6, 14, 42, 67, 96 hr) after
drug withdrawal or after
flumazenil administration. In addition, changes in sensitivity to the
convulsant effect of a
beta-carboline (
beta-CCM) were measured. Repeated treatment with
diazepam produced tolerance to its
anticonvulsant activities as indicated by shifts of the dose-response curves by
a factor of 3-5. After discontinuation of
diazepam treatment, spontaneous withdrawal occurred within 24 hr and lasted 67 hr as indicated by decreases in the threshold for convulsions induced by
isoniazid and
pentylenetetrazole.
Flumazenil-induced withdrawal was observed in both
isoniazid and
pentylenetetrazole-induced convulsion models.
Hypersensitivity of mice to the
convulsant effect of
beta-CCM also occurred. In contrast, repeated treatment with
alpidem did not produce tolerance to its
anticonvulsant effects and neither spontaneous nor
flumazenil-induced withdrawal was observed in the
pentylenetetrazole and
isoniazid models. Moreover, withdrawal of
alpidem did not induce any change in the
convulsant activity of
beta-CCM. These differences between
alpidem and
diazepam may be related to the low level of receptor occupancy during repeated treatment with
alpidem because of its selectivity for omega 1 (BZ1) sites and to its moderate intrinsic activity.