title: 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 D(1) and D(2) receptor binding in prefrontal cortex (PFC). Extrastriatal neocortical receptor D(1) (D(1)R) and D(2) (D(2)R) binding were assayed by [(11)C]NNC112 and [(11)C]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 [(11)C]NNC112 binding to PFC D(1)R, chronic daily treatment increased binding about 14% (P<.05). Acute MK-801 dose-dependently decreased [(11)C]FLB457 binding about 35% (P<.01) to PFC D(2)R; 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, D(1)R binding is increased, whereas D(2)R binding is not.
authors.affiliation: Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishiyama
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumoto
authors.forename: Kengo
authors.initials: K
authors.lastname: Sato
authors.forename: Takeharu
authors.initials: T
authors.lastname: Kakiuchi
authors.forename: Edward F
authors.initials: EF
authors.lastname: Domino
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001552:Benzazepines / Q000493:pharmacokinetics; D001572:Benzofurans / Q000493:pharmacokinetics; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D018698:Glutamic Acid / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000503:physiopathology; D008570:Memory, Short-Term / Q000187:drug effects*; D017551:Microdialysis / Q000379:methods; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D011485:Protein Binding / Q000187:drug effects; D011759:Pyrrolidines / Q000493:pharmacokinetics; D011869:Radioligand Assay / Q000379:methods; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012457:Salicylamides / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
chemical_list: D001552:Benzazepines; D001572:Benzofurans; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D011759:Pyrrolidines; D017447:Receptors, Dopamine D1; D012457:Salicylamides; D014316:Tritium; C065065:FLB 457; C077123:NNC 112; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D004298:Dopamine