Differential effects of two NMDA receptor antagonists on cognitive–behavioral development in nonhuman primates I

• Published in: Neurotoxicology and teratology Vol. 23; no. 4; pp. 319 - 332
• Main Authors: Popke, E.J, Allen, R.R, Pearson, E.C, Hammond, T.G, Paule, M.G
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 2001; Elsevier Science
• Subjects: Acetamides - pharmacology; Animals; Biological and medical sciences; Cognition - drug effects; Cognition - physiology; dizocilpine maleate; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug toxicity and drugs side effects treatment; Excitatory Amino Acid Antagonists - pharmacology; Fast sodium channels; Female; Learning; Macaca mulatta; Male; Medical sciences; MK-801; Motivation; N-methyl- d-aspartate (NMDA); Neuroprotective Agents - pharmacology; Operant behavior; Pharmacology. Drug treatments; Pregnancy; Prenatal Exposure Delayed Effects; Primates; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Reinforcement (Psychology); Remacemide; Time Factors; Toxicity: nervous system and muscle; Learning; MK-801; Remacemide; Motivation; N-methyl- d-aspartate (NMDA); Operant behavior; Fast sodium channels; Nervous system diseases; Cognitive disorder; Toxicity; Dizocilpine; Monkey; Oral administration; Developmental disorder; Long term; Young animal; Vertebrata; Mammalia; Acquisition process; Learning disability; Primates; Development; Antagonist; NMDA receptor
• ISSN: 0892-0362; 1872-9738
• DOI: 10.1016/S0892-0362(01)00156-8

The present experiment examined effects of chronic exposure to remacemide (an N-methyl- d-aspartate [NMDA] antagonist which also blocks fast sodium channels) or MK-801 (which blocks NMDA receptors, exclusively) on learning and motivation in young rhesus monkeys. Remacemide (20 or 50 mg/kg/day) or MK-801 (0.1 or 1.0 mg/kg/day) was administered every day to separate groups of animals via orogastric gavage for up to 2 years. Immediately prior to dosing, 5 days per week (M–F), throughout the 2-year dosing period, an incremental repeated acquisition (IRA) task was used to assess learning and a progressive ratio (PR) task was used to assess motivation. The results indicate an effect of 50 mg/kg/day remacemide to impair learning (IRA) which persisted even after drug treatment was discontinued. MK-801 had no effect on learning but transiently increased motivation. Because the effects of remacemide occurred independently of changes in motivation or response rates, they are likely due to specific cognitive impairments and are not due to an inability of subjects to fulfill the motoric requirements of the task. The fact that MK-801 did not alter learning suggests that NMDA antagonism alone may be insufficient to produce learning deficits in young monkeys and that such deficits may rely on the ancillary blockade of fast sodium channels.