Löscher W, Rundfeldt C, Hönack D, Ebert U
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
J Pharmacol Exp Ther. 1996 Nov;279(2):561-72.
We have reported recently that the seizure model and experimental protocol may markedly influence anticonvulsant tolerance and withdrawal characteristics of benzodiazepine (BDZ) receptor ligands so that predictions on tolerance and dependence liability of novel drugs should be based on a battery of chronic experiments. In the present study, we compared BDZ receptor ligands with different intrinsic efficacy and/or gamma-aminobutyric acidA/BDZ receptor subtype selectivity in two seizure models, by using different experimental approaches to assess the tolerance and dependence liability. In one approach, mice were chronically treated with either diazepam, clonazepam, clobazam or the novel anxiolytic and anticonvulsant beta-carboline derivative abecarnil for 4 weeks, at doses which were about equipotent to increase the threshold for myoclonic seizures induced by pentylenetetrazole. Anticonvulsant activity was determined several times during the period of chronic treatment as well as up to 2 weeks after termination of treatment in the same group of animals per drug. The threshold for electroshock-induced tonic seizures was used as a second seizure model in separate groups of mice. In another approach, drug treatment protocols were the same but the seizures were induced only twice during the 4-week period of treatment to reduce the number of trials which could lead to "learned" tolerance. In additional groups of mice, the seizure thresholds were only determined before and after the period of treatment to assess whether repeated seizure induction during the chronic treatment affects the development of dependence. All four drugs lost anticonvulsant activity during the chronic treatment in the different models and experimental approaches, without indication for a significant involvement of learned tolerance. However, marked protocol-related differences were seen with respect to withdrawal symptoms, i.e., measures of physical dependence-inducing properties of the different drugs. For instance, the pentylenetetrazole model was more sensitive than the electroshock-induced tonic seizures model to detect significant decreases in the seizure threshold in the withdrawal period. Both in terms of tolerance- and dependence-inducing properties and adverse effects seen during the chronic treatment in mice, abecarnil did not seem to offer clear advantages compared to the more traditional BDZ receptor ligands. The data substantiate the importance of study design for obtaining predictable informations on the tolerance and withdrawal characteristics of BDZ receptor ligands.
我们最近报道，癫痫发作模型和实验方案可能会显著影响苯二氮䓬（BDZ）受体配体的抗惊厥耐受性和撤药特性，因此对新药耐受性和依赖性倾向的预测应基于一系列慢性实验。在本研究中，我们通过使用不同的实验方法来评估耐受性和依赖性倾向，比较了在两种癫痫发作模型中具有不同内在效能和/或γ-氨基丁酸A/BDZ受体亚型选择性的BDZ受体配体。在一种方法中，小鼠连续4周接受地西泮、氯硝西泮、氯巴占或新型抗焦虑和抗惊厥β-咔啉衍生物阿贝卡尼治疗，剂量约为等效剂量，以提高戊四氮诱导的肌阵挛性癫痫发作阈值。在慢性治疗期间以及每种药物的同一组动物治疗终止后长达2周的时间内，多次测定抗惊厥活性。电击诱导的强直性癫痫发作阈值在另一组小鼠中用作第二种癫痫发作模型。在另一种方法中，药物治疗方案相同，但在4周治疗期间仅诱导癫痫发作两次，以减少可能导致“习得性”耐受性的试验次数。在另外几组小鼠中，仅在治疗期前后测定癫痫发作阈值，以评估慢性治疗期间反复诱导癫痫发作是否会影响依赖性的发展。在不同模型和实验方法的慢性治疗期间，所有四种药物均失去抗惊厥活性，未显示习得性耐受性有显著影响。然而，在撤药症状方面，即不同药物诱导身体依赖性特性的指标，观察到与方案相关的显著差异。例如，戊四氮模型比电击诱导的强直性癫痫发作模型更敏感，能够检测到撤药期癫痫发作阈值的显著降低。无论是在耐受性和依赖性诱导特性方面，还是在小鼠慢性治疗期间观察到的不良反应方面，与更传统的BDZ受体配体相比，阿贝卡尼似乎都没有明显优势。这些数据证实了研究设计对于获得关于BDZ受体配体耐受性和撤药特性的可预测信息的重要性。
