Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
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This research was supported by the Institut de Recherche Servier.
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Pouget, P., Wattiez, N., Rivaud-Péchoux, S. et al. Rapid development of tolerance to sub-anaesthetic dose of ketamine: an oculomotor study in macaque monkeys. Psychopharmacology 209, 313–318 (2010). https://doi.org/10.1007/s00213-010-1797-8
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DOI: https://doi.org/10.1007/s00213-010-1797-8