Differential effects of two NMDA receptor antagonists on cognitive-behavioral development in nonhuman primates I.
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.
Popke
E J
EJ
Division of Neurotoxicology, HFT-132, National Center for Toxicological Research, US FDA, 3900 NCTR Road, Jefferson, AR 72079, USA.
Allen
R R
RR
Pearson
E C
EC
Hammond
T G
TG
Paule
M G
MG
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D008253:Macaca mulatta; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011323:Primates; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012054:Reinforcement, Psychology; D013997:Time Factors
D000081:Acetamides; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C067553:remacemide