Auta James, Costa Erminio, Davis John M, Guidotti Alessandro
Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor St, Chicago, IL 60612, USA.
Neuropharmacology. 2005 Sep;49(3):425-9. doi: 10.1016/j.neuropharm.2005.04.005.
Flumazenil (FLU), a specific benzodiazepine (BZ) receptor antagonist has been used in the treatment of acute BZ intoxication or the alleviation of BZ-induced withdrawal syndrome on the basis of its weak partial agonist action at GABA(A) receptors. However, given to patients, FLU can worsen diazepam-induced withdrawal syndrome by lowering seizure threshold. We therefore investigated whether imidazenil, a selective positive allosteric modulator of GABA action at GABA(A) receptors containing alpha5 subunit, can antagonize diazepam-induced sedative action and suppression of locomotor activity without affecting diazepam anti-bicuculline action. We report here that while FLU (16.5 micromol/kg) showed no effect on locomotor activity and bicuculline-induced convulsion, it completely antagonized diazepam (10.5 micromol/kg) anti-bicuculline action and the suppression of locomotor activity. However, imidazenil (0.76 micromol/kg) elicited anti-bicuculline action and was dose-dependently antagonized by FLU (16.5 and 33 micromol/kg). Furthermore, imidazenil showed no effect on path length traveled but slightly decreased (40%) horizontal activity when compared to diazepam (85%), and maintained the anti-bicuculline action of diazepam to a threshold level similar to that observed with diazepam. Whereas cross-tolerance between BZs has been reported in animals and humans, we previously reported the absence of cross-tolerance between imidazenil and diazepam. Thus, we suggest that imidazenil might be more effective than FLU at alleviating the withdrawal syndrome associated with long-term BZ administration.
氟马西尼（FLU）是一种特异性苯二氮䓬（BZ）受体拮抗剂，因其对GABA（A）受体具有微弱的部分激动作用，已被用于治疗急性BZ中毒或缓解BZ诱导的戒断综合征。然而，给患者使用氟马西尼会通过降低癫痫阈值而加重地西泮诱导的戒断综合征。因此，我们研究了咪达唑仑（一种对含α5亚基的GABA（A）受体具有选择性正变构调节作用的GABA调节剂）是否能拮抗地西泮诱导的镇静作用和运动活动抑制，而不影响地西泮的抗荷包牡丹碱作用。我们在此报告，虽然氟马西尼（16.5微摩尔/千克）对运动活动和荷包牡丹碱诱导的惊厥没有影响，但它完全拮抗了地西泮（10.5微摩尔/千克）的抗荷包牡丹碱作用和运动活动抑制。然而，咪达唑仑（0.76微摩尔/千克）产生了抗荷包牡丹碱作用，并被氟马西尼（16.5和33微摩尔/千克）剂量依赖性拮抗。此外，与地西泮（85%）相比，咪达唑仑对行进路径长度没有影响，但水平活动略有下降（40%），并将地西泮的抗荷包牡丹碱作用维持在与地西泮观察到的阈值水平相似的水平。虽然在动物和人类中已报道BZ之间存在交叉耐受性，但我们之前报道咪达唑仑和地西泮之间不存在交叉耐受性。因此，我们认为咪达唑仑在缓解与长期使用BZ相关的戒断综合征方面可能比氟马西尼更有效。
