Behavioral effects of ketamine, an NMDA glutamatergic antagonist, in non-human primates

Shiigi, Yasuyuki; Casey, Dympna

doi:10.1007/s002130051089

Cited by 31 publications

(24 citation statements)

References 30 publications

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“…Previous work has demonstrated that subanesthetic doses of ketamine impair cognition in monkeys (Shiigi and Casey, 1999;Taffe et al, 2002). We asked whether ketamine in monkeys might model some of the specific impairments of executive control observed in schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

“…At doses of 5-10 mg/kg, ketamine acts as a dissociative agent. Subcutaneous doses of 1 mg/kg but not 0.5 mg/kg produce signs of dystonia, bradykinesia, and impaired locomotor activity (Shiigi and Casey, 1999). Taffe et al (2002) found impaired performance in monkeys trained on a neuropsychological test battery at ketamine doses of 1 mg/kg but not at 0.3 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

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Effects of the NMDA Antagonist Ketamine on Task-Switching Performance: Evidence for Specific Impairments of Executive Control

Stoet

Snyder

2005

Neuropsychopharmacol

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In humans, the effects of subanesthetic doses of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, substantially impair executive control functions. Here, we consider whether ketamine exposure can provide an animal model for the effects of ketamine on executive control. Two monkeys (Macaca mulatta) performed a cued task-switching paradigm. We studied their behavior before and after a range of ketamine doses. We found that ketamine slowed overall performance and decreased overall accuracy, strongly impaired the capacity to ignore task-irrelevant information and, to a lesser degree, decreased accuracy when a task switch was required. This pattern of results is very similar to that found in studies of schizophrenic patients performing task-switching paradigms or the Stroop task. We conclude that ketamine in monkeys provides a good animal model for exploring the relationship between the glutamate system, executive control, and the symptoms of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Effects of the NMDA Antagonist Ketamine on Task-Switching Performance: Evidence for Specific Impairments of Executive Control

Stoet

Snyder

2005

Neuropsychopharmacol

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“…Between the control block and the treatment block, animals randomly received an intramuscular injection of ketamine (Ketaset; 0.25, 0.5, 0.75, or 1 mg/kg diluted to 0.3 ml with saline), 0.3 ml of saline solution (0.9% sodium chloride) as a vehicle control, or no injection (to control for waning motivation as the animals became more satiated). Although ketamine is a dissociative anesthetic, doses Յ1.0 mg/kg have been reported not to cause debilitating effects on behavior while reliably affecting saccade latency and metrics (Shiigi and Casey, 1999;Condy et al, 2005;Stoet and Snyder, 2006;Brunamonti et al, 2007). Data were collected from three sessions per treatment per monkey, with the exception of one additional session collected from monkey G with a ketamine dose of 1.0 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

Beneficial Effects of the NMDA Antagonist Ketamine on Decision Processes in Visual Search

Shen¹,

Kalwarowsky²,

Clarence³

et al. 2010

Journal of Neuroscience

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The ability of sensory-motor circuits to integrate sensory evidence over time is thought to underlie the process of decision-making in perceptual discrimination. Recent work has suggested that the NMDA receptor contributes to mediating neural activity integration. To test this hypothesis, we trained three female rhesus monkeys (Macaca mulatta) to perform a visual search task, in which they had to make a saccadic eye movement to the location of a target stimulus presented among distracter stimuli of lower luminance. We manipulated NMDA-receptor function by administering an intramuscular injection of the noncompetitive NMDA antagonist ketamine and assessed visual search performance before and after manipulation. Ketamine was found to lengthen response latency in a dose-dependent fashion. Surprisingly, it was also observed that response accuracy was significantly improved when lower doses were administered. These findings suggest that NMDA receptors play a crucial role in the process of decision-making in perceptual discrimination. They also further support the idea that multiple neural representations compete with one another through mutual inhibition, which may explain the speedaccuracy trade-off rule that shapes discrimination behavior: lengthening integration time helps resolve small differences between choice alternatives, thereby improving accuracy.

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“…It must be acknowledged, however, that the lack of effect of ketamine on the 4-stimulus trials may also be attributed to an artifact of the experimental design. Ketamine has a relatively rapid pharmacokinetic profile in monkeys and a recent study of non-operant behaviors has demonstrated that effects of single subanaesthetic doses peak approximately 10 minutes post injection and last approximately 40-50 minutes (Shiigi and Casey 1999). Since the vsPAL difficulty conditions are evaluated in sequential order it is possible that the more difficult trials were consistently completed at lower CNS drug concentrations compared with the easier trials.…”

Section: Ketaminementioning

confidence: 99%

Differential muscarinic and NMDA contributions to visuo-spatial paired-associate learning in rhesus monkeys

et al. 2002

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Rationale-Early, accurate detection of degenerative neurological disorders such as Alzheimer's Disease (AD) is essential for therapies designed to slow disease progression. Performance of a touch-screen mediated visuo-spatial paired-associates learning (vsPAL) task predicts neurocognitive decline in elderly populations presenting with mild cognitive impairment and distinguishes AD patients from elderly depressed individuals. Translation of this cognitive task to a nonhuman model may therefore provide an improved tool for study of the etiology and treatment of dementia.Objective-The goal of the current study was to contrast cholinergic and glutamatergic contributions to performance of this AD-sensitive task by challenging rhesus monkeys performing vsPAL with muscarinic antagonist and non-competitive NMDA antagonist drugs.Methods-Monkeys (7) were trained to perform vsPAL and then serially challenged with acute doses of scopolamine (3, 10, 17 µg/kg, i.m.) and ketamine (0.3, 1.0, 1.78 mg/kg, i.m.).Results-Scopolamine produced a dose × difficulty related impairment of both recognition memory and incremental acquisition aspects of task performance. In contrast, ketamine administration resulted in a dose-dependent impairment of recognition memory but not incremental acquisition.Conclusions-Monkeys' performance of a task sensitive to AD in humans was impaired by two classic pharmacological models of cognitive impairment therefore supporting the use of this nonhuman model to explore mechanisms of AD-associated cognitive decline. The differential pattern of impairment observed is consistent with a hypothesis that muscarinic mechanisms are required for linking external events with an existing internal representation, whereas NMDA mechanisms are required for the formation/strengthening of such an internal representation.

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Behavioral effects of ketamine, an NMDA glutamatergic antagonist, in non-human primates

Abstract: These results suggest that ketamine-induced behavioral effects in non-human primates offer a model for studying a glutamatergic role in motor and mental function such as attention or perception.

Cited by 31 publications

References 30 publications

Effects of the NMDA Antagonist Ketamine on Task-Switching Performance: Evidence for Specific Impairments of Executive Control

Effects of the NMDA Antagonist Ketamine on Task-Switching Performance: Evidence for Specific Impairments of Executive Control

Beneficial Effects of the NMDA Antagonist Ketamine on Decision Processes in Visual Search

Differential muscarinic and NMDA contributions to visuo-spatial paired-associate learning in rhesus monkeys

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