Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions

Biol Psychiatry. 2000 Jan 15;47(2):137-43. doi: 10.1016/s0006-3223(99)00097-9.


Background: The demands of the Wisconsin Card Sorting Test (WCST) change with experience. This report contains two studies designed to examine N-methyl-D-aspartate (NMDA) receptor contributions to the executive components of WCST performance. These aspects of WCST performance figure more prominently in the initial completion of this task than in subsequent task repetitions in healthy populations.

Methods: In the first study, healthy subjects (n = 15) completed the WCST on two occasions separated by 1 week. In the second study, healthy subjects (n = 22) completed two test days spaced by approximately 1 week, during which, they completed the WCST and other assessments after administration of the NMDA antagonist ketamine (intravenous bolus 0.26 mg/kg followed by infusion of 0.65 mg/kg/hour) or matched placebo.

Results: In the first study, subjects reduced the number of total and perseverative errors with a single repetition of the WCST. In the second study, ketamine significantly increased the number of total errors and the number and percent of perseverative errors on the first, but not the second test day. Similarly, it reduced the number of category criteria met on the first, but not second test day. Ketamine also increased distractibility, impaired recall, produced psychosis, altered perception, and had effects resembling the negative symptoms of schizophrenia. However, only WCST performance showed order dependency.

Conclusions: This order dependency further implicates NMDA receptors in executive cognitive functions associated with the frontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Anesthetics, Dissociative / adverse effects*
  • Arousal / drug effects
  • Cognition Disorders / chemically induced*
  • Cognition Disorders / diagnosis
  • Female
  • Humans
  • Ketamine / adverse effects*
  • Learning / drug effects*
  • Male
  • Neuropsychological Tests
  • Psychomotor Performance / drug effects
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*


  • Anesthetics, Dissociative
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine