1. ¹Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan
2. ²Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA

Correspondence: Dr EF Domino, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109-0632, USA. Tel: +734 764 9115; Fax: +734 763 4450; E-mail: efdabcde@umich.edu

Received 16 September 2004; Revised 10 February 2005; Accepted 14 February 2005; Published online 20 April 2005.

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<.05). Acute MK-801 dose-dependently decreased [¹¹C]FLB457 binding about 35% (P<.01) to PFC D₂R; chronic treatment had no significant effect. Microdialysis analyses demonstrated that acute single doses of MK-801 (0.03 and 0.1 mg/kg) increased extracellular glutamate and dopamine (DA) levels in PFC. Chronic MK-801 gradually lowered glutamate and DA levels in PFC. The results demonstrate in conscious, unanesthetized primates that MK-801 induces impairment of PFC function, as measured by working memory performance. Furthermore, in response to lowered levels of DA in PFC, D₁R binding is increased, whereas D₂R binding is not.