File S E, Hitchcott P K
Psychopharmacology Research Unit, UMDS, University of London, Guy's Hospital, UK.
Psychopharmacology (Berl). 1990;101(4):525-32. doi: 10.1007/BF02244232.
Repeated administration of benzodiazepines (BDZs) produces dependence in man and animals and this is reflected in the phenomena of tolerance and withdrawal responses. In BDZ-dependent animals the BDZ-receptor antagonist flumazenil (Ro 15-1788) reverses the increased anxiety and decreased seizure threshold seen when benzodiazepine treatment is withdrawn. In contrast are reports that flumaenil enhances BDZ-withdrawal responses. Indirect influences on the direction of flumazenil's effects on anxiety are the duration and dose of BDZ treatment, whether tolerance has developed to its anxiolytic effect and whether there is an anxiogenic response on drug withdrawal. However, we conclude that the crucial factor is the anxiety level of the animal: when this is high flumazenil becomes anxiolytic; when this is low flumazenil is anxiogenic. These bidirectional effects of flumazenil can be seen in drug-naive and BDZ-dependent animals. We propose a theory of benzodiazepine dependence that can account for anxiogenic responses on drug withdrawal and for flumazenil's bidirectional effects; central to this theory is the assumption that flumazenil normalises the benzodiazepine receptor, returning it to a baseline state. Thus it is whether an animal's score lies above or below this baseline that will determine the direction of flumazenil's effect. The clinical implications of this theory are discussed. We suggest that during the development of benzodiazepine dependence, two independent adaptive biochemical mechanisms are triggered: one underlying the development of tolerance to the anxiolytic responses, the other underlying the incidence of increased anxiety on drug withdrawal. It is only changes in the latter that are induced by the administration of flumazenil.
反复给予苯二氮䓬类药物（BDZs）会导致人和动物产生依赖性，这在耐受性和戒断反应现象中有所体现。在对BDZ产生依赖的动物中，BDZ受体拮抗剂氟马西尼（Ro 15 - 1788）可逆转撤停苯二氮䓬类药物治疗时出现的焦虑增加和癫痫阈值降低的现象。然而，有报告称氟马西尼会增强BDZ的撤药反应。对氟马西尼抗焦虑作用方向的间接影响因素包括BDZ治疗的持续时间和剂量、是否已对其抗焦虑作用产生耐受性以及撤药时是否存在致焦虑反应。不过，我们得出的结论是，关键因素是动物的焦虑水平：当焦虑水平高时，氟马西尼具有抗焦虑作用；当焦虑水平低时，氟马西尼则具有致焦虑作用。氟马西尼的这种双向作用在未接触过药物的动物和对BDZ产生依赖的动物中均可见到。我们提出了一种苯二氮䓬类药物依赖理论，该理论可以解释撤药时的致焦虑反应以及氟马西尼的双向作用；该理论的核心假设是氟马西尼使苯二氮䓬类受体正常化，使其恢复到基线状态。因此，动物的分数是高于还是低于该基线将决定氟马西尼作用的方向。本文讨论了该理论的临床意义。我们认为，在苯二氮䓬类药物依赖的发展过程中，会触发两种独立的适应性生化机制：一种是对抗焦虑反应产生耐受性的基础，另一种是撤药时焦虑增加发生率的基础。只有后者的变化是由氟马西尼的给药所诱发的。
