The purpose of the present study was to evaluate the efficacy of rapastinel, an allosteric modulator of NMDA receptor function, to accelerate the loss of opioid withdrawal symptoms and blunt or prevent relapse to morphine conditioned place preference (CPP) in rats. Two studies were conducted. In study 1, adult and adolescent male and female rats were treated with increasing doses of morphine (5 mg/kg, bid to 25 mg/kg bid) for 5 days. On day 6 animals were treated with naloxone (1 mg/kg) and withdrawal was assessed. They were then treated with saline or rapastinel (5 mg/kg) on days 6 and 8, and withdrawal assessed on day 9. Rapastinel treated animals exhibited significantly lower levels of withdrawal signs on day 9. No sex or age differences were observed. In Study 2, CPP for morphine was established in adult rats (males and females) by 4 daily pairings with saline and morphine (am/pm alternation). They were tested for CPP on day 5, and then treated with rapastinel (5 mg/kg) or saline daily on days 6-10 of extinction. On day 11 they received a final dose of rapastinel or saline followed by extinction. On day 12, animals received 1 mg/kg of morphine and were tested for relapse. Rapastinel did not affect extinction of CPP, but rapastinel-treated animals spent significantly less time in the previously morphine-paired side than saline-treated animals during the relapse trial. These findings of accelerated loss of withdrawal signs and blunted relapse to CPP suggest that rapastinel could provide an adjunctive therapy for opioid dependence during initiation of pharmacotherapy for opioid dependence.

中文翻译：

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Rapastinel 在重复吗啡后加速戒断症状的丧失，并抑制复发到条件性场所偏好

本研究的目的是评估 rapastinel（一种 NMDA 受体功能的变构调节剂）在大鼠中加速阿片类药物戒断症状的丧失以及减弱或预防吗啡条件性位置偏好 (CPP) 复发的功效。进行了两项研究。在研究 1 中，成年和青春期雄性和雌性大鼠用增加剂量的吗啡（5 mg/kg，bid 至 25 mg/kg bid）治疗 5 天。在第 6 天，用纳洛酮 (1 mg/kg) 治疗动物并评估戒断情况。然后在第 6 天和第 8 天用盐水或 rapastinel (5 mg/kg) 处理它们，并在第 9 天评估戒断情况。 Rapastinel 治疗的动物在第 9 天表现出显着降低的戒断迹象。没有观察到性别或年龄差异。在研究 2 中，通过每天 4 次与生理盐水和吗啡配对（上午/下午交替）在成年大鼠（雄性和雌性）中建立吗啡的 CPP。在第 5 天对它们进行 CPP 测试，然后在灭绝的第 6-10 天每天用 rapastinel (5 mg/kg) 或盐水处理。在第 11 天，他们接受了最后一剂 rapastinel 或生理盐水，然后消退。在第 12 天，动物接受 1 mg/kg 吗啡并进行复发测试。Rapastinel 不影响 CPP 的消失，但在复发试验期间，rapastinel 治疗的动物在先前吗啡配对的一侧花费的时间明显少于盐水治疗的动物。这些戒断症状加速消失和 CPP 复发迟缓的发现表明，在阿片类药物依赖的药物治疗开始期间，rapastinel 可以为阿片类药物依赖提供辅助治疗。