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

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

doi:10.1007/s00213-010-1797-8

Cited by 42 publications

(29 citation statements)

References 18 publications

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“…For example, the sample size in this study and physiological noise may have influenced the reliability, variability and power estimates calculated due to undue influence of outliers and impaired variance estimates. In addition, reliability could be affected by the development of a tolerance to the effects of ketamine (Pouget et al, 2010), although the results in this study, such as the lack of session effects in both behavioural and imaging data, suggest that tolerance did not occur. Furthermore, exclusion of females from the sample may also influence the generalisability of the results, as gender has been shown to affect the response to ketamine (Morgan et al, 2006).…”

Section: Limitationscontrasting

confidence: 67%

Test–retest reliability of the BOLD pharmacological MRI response to ketamine in healthy volunteers

et al. 2013

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Section: Limitationscontrasting

confidence: 67%

Test–retest reliability of the BOLD pharmacological MRI response to ketamine in healthy volunteers

et al. 2013

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“…Lim and colleagues[54] describe a case series of two patients with chronic exposure to ketamine averaging 4–5 months, who report enhanced sensation of environmental stimuli (e.g., taste, smells, music) observed in many acute studies but also report the occurrence of true auditory, visual, and tactile hallucinations with chronic use. Chronic exposure leads to tolerance to sub-anesthetic ketamine [55]. In prior work we speculated that acute and chronic ketamine differ in their impact on processes of learning and inference [29].…”

Section: Discussionmentioning

confidence: 99%

Ketamine-Induced Hallucinations

Powers

Gancsos²,

Finn³

et al. 2015

Psychopathology

100

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Background: Ketamine, the NMDA glutamate receptor antagonist drug, is increasingly employed as an experimental model of psychosis in healthy volunteers. At subanesthetic doses, it safely and reversibly causes delusion-like ideas, amotivation and perceptual disruptions reminiscent of the aberrant salience experiences that characterize first-episode psychosis. However, auditory verbal hallucinations, a hallmark symptom of schizophrenia, have not been reported consistently in healthy volunteers even at high doses of ketamine. Sampling and Methods: Here we present data from a set of healthy participants who received moderately dosed, placebo-controlled ketamine infusions in the reduced stimulation environment of the magnetic resonance imaging (MRI) scanner. We highlight the phenomenological experiences of 3 participants who experienced particularly vivid hallucinations. Results: Participants in this series reported auditory verbal and musical hallucinations at a ketamine dose that does not induce auditory hallucination outside of the scanner. Conclusions: We interpret the observation of ketamine-induced auditory verbal hallucinations in the context of the reduced perceptual environment of the MRI scanner and offer an explanation grounded in predictive coding models of perception and psychosis - the brain fills in expected perceptual inputs, and it does so more in situations of altered perceptual input. The altered perceptual input of the MRI scanner creates a mismatch between top-down perceptual expectations and the heightened bottom-up signals induced by ketamine. Such circumstances induce aberrant percepts, including musical and auditory verbal hallucinations. We suggest that these circumstances might represent a useful experimental model of auditory verbal hallucinations and highlight the impact of ambient sensory stimuli on psychopathology.

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“…We previously performed titration experiments with each monkey to determine animalspecific concentrations of ketamine (between 0.2 and 1.0 mg/kg) for the experiment, as these values have previously been found to elicit cognitive deficits with minimal anesthetic effects (Condy et al, 2005). Monkey W had more exposure to ketamine before this study for surgeries and routine veterinary procedures and developed a greater tolerance to the drug (Pouget et al, 2010). The behavioral effects of ketamine became apparent after ϳ5 min (50 -75 trials).…”

Section: Methodsmentioning

confidence: 99%

NMDA Antagonist Ketamine Reduces Task Selectivity in Macaque Dorsolateral Prefrontal Neurons and Impairs Performance of Randomly Interleaved Prosaccades and Antisaccades

Skoblenick¹,

Everling

2012

J. Neurosci.

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Ketamine, an NMDA receptor antagonist, has been shown to induce behavioral abnormalities in humans that mimic the positive, negative, and most importantly cognitive deficits observed in schizophrenia. Similar cognitive deficits have been observed in nonhuman primates after a subanesthetic dose of ketamine, including an impairment in their ability to perform the antisaccade task, which requires the suppression of a prosaccade toward a flashed stimulus and the generation of a saccade in the opposite direction. The neural basis underlying these cognitive impairments remains unknown. Here, we recorded single-neuron activity in the lateral prefrontal cortex of macaque monkeys before and after the administration of subanesthetic doses of ketamine during the performance of randomly interleaved prosaccade and antisaccade trials. Ketamine impeded the monkeys' ability to maintain and apply the correct task rule and increased reaction times of prosaccades and antisaccades. These behavioral changes were associated with an overall increase in activity of PFC neurons and a reduction in their task selectivity. Our results suggest that the mechanism underlying ketamine-induced cognitive abnormalities may be the nonspecific increase in PFC activity and the associated reduction of task selectivity.

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

Abstract: 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.

Cited by 42 publications

References 18 publications

Test–retest reliability of the BOLD pharmacological MRI response to ketamine in healthy volunteers

Test–retest reliability of the BOLD pharmacological MRI response to ketamine in healthy volunteers

Ketamine-Induced Hallucinations

NMDA Antagonist Ketamine Reduces Task Selectivity in Macaque Dorsolateral Prefrontal Neurons and Impairs Performance of Randomly Interleaved Prosaccades and Antisaccades

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