The treatment of opioid addiction is challenging because addicts are highly prone to relapse when the memory of the former drug experience is triggered by emotional or environmental cues. An emerging and promising concept in addiction biology is that by manipulating adult hippocampal neurogenesis, a phenomenon involved in learning and memory, drug reward-like behaviors and relapse can be attenuated. We tested a new synthetic compound, KHS101, in an animal model of drug-associated contextual memory. KHS101 has been reported to increase the expression of neurogenic differentiation 1 (NeuroD1), a transcription factor involved in adult neurogenesis, and to specifically induce neuronal differentiation both in vitro and in vivo. Our results indicated that the subcutaneous injection of 3 mg/kg KHS101 for 7 days before conditioned place preference (CPP) training prolonged CPP extinction, while the same treatment after training accelerated extinction. This effect paralleled that observed following temporally controlled, tetracycline-induced NeuroD1 overexpression. Furthermore, the effect of KHS101 may occur via its induction of NeuroD1 expression as demonstrated by the abolition of the KHS101-mediated modulation of morphine-induced CPP extinction after the stereotaxic injection of lentiviral NeuroD1 small interfering RNA into the dentate gyrus (DG) of the hippocampus. These results suggest that the KHS101-mediated modulation of neurogenesis at a critical stage of the conditioning or the extinction of an opioid-associated experience may disrupt the memory trace of the existing opioid-associated experience to facilitate the extinction of drug-associated contextual memory. This implies that KHS101 has therapeutic potential for the treatment of opioid addiction.

中文翻译：

---

合成小分子KHS101操纵NeuroD1表达对吗啡语境记忆的时间效应。

阿片类药物成瘾的治疗具有挑战性，因为当前一种药物经历的记忆是由情绪或环境暗示触发时，成瘾者极容易复发。成瘾生物学中一个新兴且有希望的概念是，通过操纵成年海马神经发生，可以减轻学习和记忆，药物奖励样行为和复发所涉及的现象。我们在与药物相关的背景记忆的动物模型中测试了一种新的合成化合物KHS101。据报道，KHS101可以增加神经源性分化1（NeuroD1）的表达，神经元分化1（NeuroD1）是一种参与成人神经发生的转录因子，在体外和体内均可特异性诱导神经元分化。我们的结果表明，在进行条件性位置偏爱（CPP）训练之前，皮下注射3 mg / kg KHS101持续7天可延长CPP的灭绝，而训练后的相同治疗可加速灭绝。此效果与在时间控制的四环素诱导的NeuroD1过表达后观察到的效果相似。此外，KHS101的作用可能是通过诱导NeuroD1表达而发生的，这是通过将慢病毒NeuroD1小干扰RNA立体定向注射到小鼠的齿状回（DG）中后，由KHS101介导的吗啡诱导的CPP灭绝的调节而消除的。海马。这些结果表明，在调节的关键阶段或阿片类药物相关经验的消失中，KHS101介导的神经发生调节可能会破坏现有阿片类药物相关经验的记忆轨迹，以促进药物相关背景记忆的消失。这意味着KHS101具有治疗阿片类药物成瘾的潜力。