Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys

Abstract

This study demonstrates that dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, impairs working memory of conscious behaving monkeys. In addition, acute and chronic MK-801 produces different effects on D1 and D2 receptor binding in prefrontal cortex (PFC). Extrastriatal neocortical receptor D1 (D1R) and D2 (D2R) binding were assayed by [11C]NNC112 and [11C]FLB457, respectively, using high-specific radioactivity and a specially designed monkey positron emission tomograph (PET). Acute single dose (0.03, 0.1, and 0.3 mg/kg) i.v. administration of MK-801 resulted in dose-related impairment of working memory performance of an oculomotor delayed response (ODR) task. There was no impairment of performance of a visually guided saccade (VGS) task with low doses of 0.03 and 0.1, but it was depressed with 0.3 mg/kg. Chronic daily MK-801 (0.03 mg/kg, i.m., b.i.d. for 13 days) induced impaired ODR task performance with no effect on the VGS task. Although acute single doses of MK-801 caused no significant changes in [11C]NNC112 binding to PFC D1R, chronic daily treatment increased binding about 14% (P