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

Abstract

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.

Electrophysiological evidence of atypical processing underlying mental set shifting in ecstasy polydrug and polydrug users.

“…Although we attempted to control for this with the addition of a polydrug control group, it was apparent that the ecstasy user group smoked significantly more cannabis and consumed significantly more cocaine than this group. Furthermore there were 9 participants in the ecstasy user group who reported using ketamine in the last 30 days, compared to none in the polydrug group, this is potentially problematic for the interpretation of the current results given the association between ketamine use and executive function deficits in humans (for a review see Morgan & Curran, 2006), and specifically that switching has been shown to be impaired in animals with ketamine exposure (Stoet & Snyder, 2006).…”

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

“…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.…”

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

“…Reduced cognitive function is considered to be the most debilitating aspect of schizophrenia as the severity of these symptoms directly relates to the patient's quality of life and current pharmaceutical interventions provide minimal improvement (Elvevåg and Goldberg, 2000;Goldman-Rakic et al, 2004;Goeree et al, 2005;van Os and Kapur, 2009). Nonhuman primates also show similar cognitive deficits following systemic subanesthetic doses of ketamine as patients with schizophrenia in a number of behavioral tasks (Condy et al, 2005;Stoet and Snyder, 2006). An example is the antisaccade paradigm, which requires the inhibition of a prepotent prosaccade toward a flashed peripheral stimulus in favor of the generation of a saccade away from the stimulus toward the opposite direction (Everling and Fischer, 1998;Munoz and Everling, 2004).…”