Division of Neurotoxicology, National Center for Toxicological Research/FDA, 3900 NCTR Road, Jefferson, AR 72079-9502, USA.
Neurotoxicol Teratol. 2011 Mar-Apr;33(2):220-30. doi: 10.1016/j.ntt.2011.01.001. Epub 2011 Jan 15.
Previously our laboratory has shown that ketamine exposure (24h of clinically relevant anesthesia) causes significant increases in neuronal cell death in perinatal rhesus monkeys. Sensitivity to this ketamine-induced neurotoxicity was observed on gestational days 120-123 (in utero exposure via maternal anesthesia) and on postnatal days (PNDs) 5-6, but not on PNDs 35-37. In the present study, six monkeys were exposed on PND 5 or 6 to intravenous ketamine anesthesia to maintain a light surgical plane for 24h and six control animals were unexposed. At 7 months of age all animals were weaned and began training to perform a series of cognitive function tasks as part of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB). The OTB tasks used here included those for assessing aspects of learning, motivation, color discrimination, and short-term memory. Subjects responded for banana-flavored food pellets by pressing response levers and press-plates during daily (M-F) test sessions (50 min) and were assigned training scores based upon their individual performance. As reported earlier (Paule et al., 2009) beginning around 10 months of age, control animals significantly outperformed (had higher training scores than) ketamine-exposed animals for approximately the next 10 months. For animals now over 3 and one-half years of age, the cognitive impairments continue to manifest in the ketamine-exposed group as poorer performance in the OTB learning and color and position discrimination tasks, as deficits in accuracy of task performance, but also in response speed. There are also apparent differences in the motivation of these animals which may be impacting OTB performance. These observations demonstrate that a single 24-h episode of ketamine anesthesia, occurring during a sensitive period of brain development, results in very long-lasting deficits in brain function in primates and provide proof-of-concept that general anesthesia during critical periods of brain development can result in subsequent functional deficits. Supported by NICHD, CDER/FDA and NCTR/FDA.
先前我们的实验室已经表明，氯胺酮暴露（24 小时的临床相关麻醉）会导致围产期恒河猴神经元细胞死亡明显增加。在妊娠第 120-123 天（通过母体麻醉进行宫内暴露）和出生后第 5-6 天（PND）观察到对这种氯胺酮诱导的神经毒性的敏感性，但在 PND 35-37 天则没有。在本研究中，六只猴子在 PND 5 或 6 天接受静脉注射氯胺酮麻醉，以维持轻手术平面 24 小时，六只对照动物未接受麻醉。在 7 个月大时，所有动物都断奶并开始接受训练，以作为国家毒理学研究中心（NCTR）操作测试电池（OTB）的一部分来执行一系列认知功能任务。这里使用的 OTB 任务包括评估学习、动机、颜色辨别和短期记忆等方面的任务。在每天（周一至周五）的测试会议（50 分钟）中，通过按压反应杆和按压板，动物通过按压反应杆和按压板来响应香蕉味的食物丸，并根据其个人表现分配训练分数。如之前报道的（Paule 等人，2009 年），大约从 10 个月大开始，对照动物的表现明显优于（训练分数高于）氯胺酮暴露的动物，大约持续了 10 个月。对于现在已经超过 3 岁半的动物，氯胺酮暴露组的认知障碍继续表现出来，在 OTB 学习、颜色和位置辨别任务中的表现较差，表现准确性不足，但反应速度也较慢。这些动物的动机也存在明显差异，这可能会影响 OTB 的表现。这些观察结果表明，单次 24 小时氯胺酮麻醉发生在大脑发育的敏感时期，会导致灵长类动物的大脑功能出现非常持久的缺陷，并提供了一个概念证明，即在大脑发育的关键时期进行全身麻醉会导致随后的功能缺陷。这项研究由美国国立卫生研究院儿童健康与人类发展研究所（NICHD）、美国食品和药物管理局药物评价和研究中心（CDER/FDA）和美国食品和药物管理局国家毒理学研究中心（NCTR/FDA）资助。
