Rapid development of tolerance to sub-anaesthetic dose of ketamine: an oculomotor study in macaque monkeys
Rapid development of tolerance to sub-anaesthetic dose of ketamine: an oculomotor study in macaque monkeys
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DOI：
10.1007/s00213-010-1797-8
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发表时间：
2010-05-01
影响因子：
3.4
通讯作者：
Gaymard, Bertrand
中科院分区：
文献类型：
--
作者：
Pouget, Pierre;Wattiez, Nicolas;Gaymard, Bertrand
氯胺酮是一种非竞争性的N-甲基-d-天冬氨酸拮抗剂，已广泛用于麻醉目的。在亚麻醉剂量下，它会诱导类似于精神分裂症的分离状态。对分离状态的这种作用的发现导致其被用作精神分裂症的药理学模型，并且也导致其被非法用作娱乐性药物。前者提供了宝贵的信息，而后者表明，氯胺酮的重复给药可诱导耐受性。令人惊讶的是，相关文献的回顾表明，耐受亚麻醉剂量的氯胺酮在很大程度上是unreported在neuropharmacological studies.In order to investigate this caveat，我们已经进行了事后分析的行为的影响引起的重复注射亚麻醉剂量的氯胺酮观察在五个连续的猴子执行两个oculantic任务。氯胺酮的影响进行了量化的动物的性能和lavonin在一个prosaccade和antisaccade任务，两个ocularies范例，是受损后ketamineadministration.Although初始注射的结果证实了一个明确的行为效应氯胺酮注射在所有猴子，随后的管理表明，耐受性最终出现在所有猴子。然而，这种耐受性的轮廓表现出很大的受试者间的variability.Psychopharmacological实验使用氯胺酮作为精神病的药理学模型，因此，应考虑这些影响在每个人的动力学和时间过程中，并考虑到在实验方案的设计。
Ketamine, a non-competitive N-methyl-d-aspartic acid antagonist, has been widely used for anaesthetic purposes. At sub-anaesthetic dosage, it induces a dissociative state similar to schizophrenia. The discovery of this effect on dissociative state has led to its use as a pharmacological model of schizophrenia and has also been responsible for its illegal use as a recreational drug. Whereas the former has provided invaluable information, the latter has demonstrated that repeated administration of ketamine induces tolerance. Surprisingly, a review of the relevant literature shows that tolerance to sub-anaesthetic doses of ketamine is largely unreported in neuropharmacological studies.In order to investigate this caveat, we have performed a post hoc analysis of the behavioural effects induced by repeated injections of sub-anaesthetic doses of ketamine observed in five consecutive monkeys performing two oculomotor tasks. Ketamine effects were quantified by the animals' performances and latencies in a prosaccade and an antisaccade task, two oculomotor paradigms that are impaired after ketamine administration.Although the result of the initial injections confirmed a clear behavioural effect of ketamine injections in all monkeys, subsequent administrations showed that a tolerance eventually appeared in all monkeys. The profile of this tolerance exhibited however a large inter-subject variability.Psychopharmacological experiments using ketamine as a pharmacological model of psychosis should therefore consider the kinetic and time course of these effects in each individuals and take them into account in the design of experimental protocols.