The Nociceptin/Orphanin FQ (N/OFQ) system has been shown to modulate various aspects of long-term memory. It is therefore important to study the effects on memory impairment by nociceptin receptor (NOP) agonists under preclinical development. In the present study, we investigated the effect of systemic injection of two small molecule selective NOP agonists, AT-202 and AT-524, in the object location memory task in male and female mice. Since high doses of NOP agonists have been shown to induce sedation, we first determined the sedative doses for the two compounds and found them to be higher in female than in male mice. We then observed that sub-sedative doses of NOP agonists administered before learning, induced memory impairment during a test session performed 24 h later. Again, female mice were less sensitive to the amnesic effects than males. On the contrary, in male mice, NOP agonists did not produce amnesia when they were injected after learning, suggesting that they do not affect the consolidation of object location memory. Finally, repeated administration of high doses of NOP agonists over 7 days did not impair long-term spatial memory. Together, our data show for the first time that NOP receptor agonists impair the acquisition of object location memory with sex-dependent potency but do not affect memory consolidation, and that repeated stimulation of the receptor does not compromise long-term episodic-like spatial memory.

伤害感受肽/孤啡宁 FQ (N/OFQ) 系统已被证明可以调节长期记忆的各个方面。因此，在临床前开发中研究伤害感受素受体（NOP）激动剂对记忆障碍的影响非常重要。在本研究中，我们研究了全身注射两种小分子选择性 NOP 激动剂 AT-202 和 AT-524 对雄性和雌性小鼠的物体位置记忆任务的影响。由于高剂量的 NOP 激动剂已被证明可以诱导镇静，我们首先确定了这两种化合物的镇静剂量，发现雌性小鼠的镇静剂量高于雄性小鼠。然后我们观察到，在学习前给予亚镇静剂量的 NOP 激动剂，会在 24 小时后进行的测试过程中诱发记忆障碍。同样，雌性小鼠对遗忘效应的敏感度低于雄性小鼠。相反，在雄性小鼠中，学习后注射NOP激动剂并没有产生失忆症，这表明它们不会影响物体位置记忆的巩固。最后，7天内重复给予高剂量NOP激动剂并不会损害长期空间记忆。总之，我们的数据首次表明，NOP 受体激动剂会损害具有性别依赖性效力的物体位置记忆的获取，但不影响记忆巩固，并且重复刺激受体不会损害长期情景式空间记忆。