Data_Sheet_1_Imepitoin Shows Benzodiazepine-Like Effects in Models of Anxiety.PDF

Imepitoin is a low affinity partial agonist for the benzodiazepine binding site of γ-aminobutyric acid (GABAA) receptors, and is currently used as an antiepileptic in dogs. Here we tested imepitoin for anxiolytic properties. In an in vitro model, imepitoin was capable of preventing the effect of corticotrophin releasing factor (CRF) on locus coeruleus neurons without suppressing the basal activity of these cells, an activity which is suggestive for an anti-stress effect of imepitoin. In addition, we applied a battery of standard rodent preclinical tests for anxiety behavior including elevated plus mazes in mice and rats, light-dark-box in mice and rats, social interaction test in rats, or the Vogel conflict test in rats. In all models, the observed profile of imepitoin appeared similar to benzodiazepines and typical for anxiolytic drugs. We also observed anxiolytic activity in dogs in a provoked open field sound-induced fear model, where reactions to noises were elicited by a sound recording of thunderstorms. Imepitoin caused an increase in locomotion measured in distance traveled and an ameliorating effect on cortisol levels in response to thunderstorm noises. For comparison, dexmedetomidine caused a decrease in locomotion and had no effect on cortisol. In all animal models the doses needed for an anxiolytic effect were not associated with sedation. In rodents, there was at least a factor of 10 between anxiolytic doses and doses with mild signs of sedation. In summary, imepitoin showed similar anxiolytic activities as benzodiazepines but without producing the known adverse reactions of benzodiazepines such as sedation.

依米匹汀（imepitoin）是γ-氨基丁酸A型受体（GABAA receptors）苯二氮䓬结合位点的低亲和力部分激动剂，目前被用作犬用抗癫痫药物。本研究针对依米匹汀的抗焦虑特性展开了测试。在体外模型中，依米匹汀能够阻断促肾上腺皮质激素释放因子（CRF）对蓝斑神经元（locus coeruleus neurons）的作用，且不会抑制此类细胞的基础活性，这一活性提示依米匹汀具备抗应激功效。此外，我们采用了一系列标准化啮齿类动物抗焦虑行为临床前实验，包括小鼠与大鼠的高架十字迷宫（elevated plus mazes）、明暗箱实验（light-dark-box）、大鼠的社交互动实验（social interaction test）以及伏格冲突实验（Vogel conflict test）。在所有实验模型中，依米匹汀的作用特征与苯二氮䓬类（benzodiazepines）药物相似，符合抗焦虑药物的典型表现。我们还在雷暴录音诱导声音恐惧的犬类诱发型开阔场恐惧模型中观察到了依米匹汀的抗焦虑活性：该模型通过录制雷暴声音来引发受试犬只的恐惧反应。依米匹汀可增加受试犬只的运动距离，并改善其在雷暴声音刺激下的皮质醇水平异常。作为对照，右美托咪定（dexmedetomidine）会降低受试犬只的运动能力，且对皮质醇水平无显著影响。在所有动物模型中，产生抗焦虑效果所需的依米匹汀剂量均未伴随镇静作用。在啮齿类动物中，抗焦虑剂量与引发轻度镇静迹象的剂量之间至少相差10倍。综上，依米匹汀展现出与苯二氮䓬类药物相似的抗焦虑活性，但不会产生苯二氮䓬类药物已知的不良反应（如镇静作用）。