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Rapid development of tolerance to sub-anaesthetic dose of ketamine: an oculomotor study in macaque monkeys.

Pierre Pouget, Nicolas Wattiez, Sophie Rivaud-Péchoux, Bertrand Gaymard

Psychopharmacology May 2010 DOI: 10.1007/s00213-010-1797-8 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Post hoc analysis of behavioural data from an experimental animal study Peer reviewed
Sample size 5
Population Monkeys performing oculomotor tasks
Intervention Ketamine
Measures prosaccade task, antisaccade task
Topics Esketamine Ketamine
Key findings Repeated sub-anaesthetic ketamine injections led to tolerance in all five monkeys, though the tolerance profile varied widely among individuals. Initial injections produced clear behavioural effects, but these diminished with subsequent administrations.

Abstract

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.

Comparable studies

Other preclinical and animal studies on ketamine, most cited first.

Study Year Design Participants
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats 2010 Observational study
Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats 1997 Dose-response study with microdialysis and behavioral testing
NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice 2016 Preclinical study
The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats 1983 Experimental study
R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice 2015 Experimental study

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Esketamine Ketamine