Perrault G, Morel E, Sanger D J, Zivkovic B
Synthelabo Recherche (L.E.R.S.), Bagneux, France.
Neuropharmacology. 1993 Sep;32(9):855-63. doi: 10.1016/0028-3908(93)90140-x.
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.
阿吡坦是一种新型的具有咪唑并吡啶结构的抗焦虑药，它对GABAA受体的ω1（BZ1）调节位点具有高亲和力。本研究调查了反复给予阿吡坦后是否会像苯二氮䓬类药物那样产生耐受性和身体依赖性。小鼠连续10天每天口服给予阿吡坦（100mg/kg）或地西泮（5mg/kg）两次。在反复给药后，通过测量对戊四氮和异烟肼诱发惊厥的拮抗作用以及荷包牡丹碱诱发的死亡率来评估耐受性。异烟肼诱发惊厥潜伏期的缩短和戊四氮最小惊厥剂量的降低被作为身体依赖性的指标，并在停药或给予氟马西尼后的不同时间（3、6、14、42、67、96小时）进行评估。此外，还测量了对β-咔啉（β-CCM）惊厥作用的敏感性变化。反复给予地西泮会产生对其抗惊厥活性的耐受性，剂量-反应曲线移位3-5倍表明了这一点。地西泮治疗停药后，24小时内出现自发戒断，并持续67小时，异烟肼和戊四氮诱发惊厥阈值的降低表明了这一点。在异烟肼和戊四氮诱发惊厥模型中均观察到氟马西尼诱发的戒断反应。小鼠对β-CCM惊厥作用的超敏反应也会出现。相比之下，反复给予阿吡坦不会产生对其抗惊厥作用的耐受性，在戊四氮和异烟肼模型中既未观察到自发戒断也未观察到氟马西尼诱发的戒断反应。此外，停用阿吡坦并未引起β-CCM惊厥活性的任何变化。阿吡坦和地西泮之间的这些差异可能与反复给予阿吡坦期间受体占有率较低有关，这是由于其对ω1（BZ1）位点的选择性及其适度的内在活性。
