Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys
Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys
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DOI：
10.1111/adb.12004
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发表时间：
2014-03-01
影响因子：
3.4
通讯作者：
Yew, David T.
中科院分区：
文献类型：
--
作者：
Sun, Lin;Li, Qi;Yew, David T.
氯胺酮是一种非竞争性的N-甲基-D-天冬氨酸受体拮抗剂，已成为全球青少年滥用药物者中越来越受欢迎的药物。现有证据表明，当对健康志愿者单次给药时，氯胺酮会对工作记忆、情景记忆和语义记忆产生急性损伤，并伴随沿着精神性和分离效应。然而，对氯胺酮对行为、认知异常和神经化学稳态可能的慢性影响的理解仍然不完全。尽管先前的人类研究表明氯胺酮可能损害一系列认知技能，但使用非人类模型进行的研究将允许更精确地探索可能导致有害影响的神经化学机制。本研究使用末端脱氧核苷酸转移酶介导的生物素化dUTP缺口末端标记（TUNEL）和凋亡标志物（包括Bax、Bcl-2和caspase-3），检查了青少年雄性食蟹猴（Macaca fascicularis）接受亚麻醉氯胺酮给药（1 mg/kg，i. v.）1或6个月后的行为异常（移动、行走、跳跃和攀爬）和前额叶皮质细胞凋亡。结果表明，与对照组相比，氯胺酮治疗6个月的猴子的运动活动减少，前额叶皮层细胞死亡增加。在1个月氯胺酮治疗组中未发现这种降低。我们的研究表明，在猴子中给予娱乐剂量的氯胺酮可能会由于神经毒性作用而导致脑功能的永久性和不可逆的缺陷，涉及前额叶皮层中凋亡途径的激活。
Ketamine, a non-competitive N-methyl-D-aspartic acid receptor antagonist, has emerged as an increasingly popular drug among young drug abusers worldwide. Available evidence suggests that ketamine produces acute impairments of working, episodic and semantic memory along with psychotogenic and dissociative effects when a single dose is given to healthy volunteers. However, understanding of the possible chronic effects of ketamine on behavior, cognitive anomalies and neurochemical homeostasis is still incomplete. Although previous human studies demonstrate that ketamine could impair a range of cognitive skills, investigation using non-human models would permit more precise exploration of the neurochemical mechanisms which may underlie the detrimental effects. The current study examined the abnormalities in behavior (move, walk, jump and climb) and apoptosis of the prefrontal cortex using terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL) and apoptotic markers, including Bax, Bcl-2 and caspase-3 in adolescent male cynomolgus monkeys (Macaca fascicularis) after 1 or 6 months of sub-anesthetic ketamine administration (1mg/kg, i.v.). Results showed that ketamine decreased locomotor activity and increased cell death in the prefrontal cortex of monkeys with 6 months of ketamine treatment when compared with the control monkeys. Such decreases were not found in the 1-month ketamine-treated group. Our study suggested that ketamine administration of recreational dose in monkeys might produce permanent and irreversible deficits in brain functions due to neurotoxic effects, involving the activation of apoptotic pathways in the prefrontal cortex.