Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan; Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan.
J Pharmacol Sci. 2019 Mar;139(3):174-179. doi: 10.1016/j.jphs.2019.01.002. Epub 2019 Jan 17.
Strategies to facilitate extinction of fear memory have attracted increasing attention for enhancing the effectiveness of exposure therapy for anxiety disorders. Previously, we demonstrated that systemic administration of a delta opioid receptor agonist, KNT-127, has clear anxiolytic-like effects in rats, without impairing memory. These observations led us to hypothesize that KNT-127 might be an appropriate therapeutic agent for anxiety disorders when combined with exposure therapy. In the present study, we demonstrate that KNT-127 (3 mg/kg) facilitates extinction learning of fear memory using the contextual fear conditioning test. As expected, a partial agonist at the glycine-binding site on the glutamatergic N-methyl-d-aspartate receptor, d-cycloserine (15 mg/kg), facilitated extinction learning of contextual fear in rats. In contrast, a benzodiazepine anxiolytic, diazepam (1 mg/kg), impaired the fear extinction learning. Interestingly, the facilitatory effect of KNT-127 on extinction learning was observed not only after a 10-min re-exposure, but also after a much shorter (2-min) re-exposure to the context, while d-cycloserine was ineffective at facilitating extinction when a short-duration exposure was given. Our findings may suggest that administration of a delta opioid receptor agonist might have therapeutic efficacy when combined with exposure therapy for treating a range of anxiety disorders.
为提高焦虑症暴露疗法的效果，促进恐惧记忆消退的策略受到越来越多的关注。此前，我们的研究表明，系统给予δ阿片受体激动剂 KNT-127，在不损害记忆的情况下，在大鼠中具有明显的抗焦虑样作用。这些观察结果使我们假设，当与暴露疗法结合使用时，KNT-127 可能是治疗焦虑症的合适药物。在本研究中，我们使用情境恐惧条件测试证明，KNT-127（3mg/kg）促进了恐惧记忆的消退学习。正如预期的那样，N-甲基-D-天冬氨酸受体甘氨酸结合部位的部分激动剂 D-环丝氨酸（15mg/kg）促进了大鼠对情境恐惧的消退学习。相比之下，苯二氮䓬类抗焦虑药地西泮（1mg/kg）损害了恐惧的消退学习。有趣的是，KNT-127 对消退学习的促进作用不仅在 10 分钟的重新暴露后观察到，而且在更短（2 分钟）的重新暴露于情境后也观察到，而 D-环丝氨酸在给予短时间暴露时对促进消退没有效果。我们的研究结果可能表明，当与暴露疗法结合使用时，给予 δ 阿片受体激动剂可能对治疗一系列焦虑症具有治疗效果。
