The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys.
IDRA 21, a positive allosteric modulator of the glutamate AMPA receptor, produced a concentration-dependent inhibition of glutamate-induced inactivation of membrane currents in recombinant HEK 293 (human embryonic kidney) cells stably transfected with human GluR1/2 flip receptors. IDRA 21 doubled the charge transfer at a concentration of 70 microM, suggesting that this compound can facilitate excitatory neurotransmission via GluR 1/2 receptors. We next sought to exploit this mechanism of action by examining the drug as a potential cognition-enhancing agent in non-human primates. Oral administration of IDRA 21 produced a highly significant improvement in the performance of a delayed matching-to-sample (DMTS) task by young adult rhesus monkeys. The pattern of task improvement over the dose range 0.15-10 mg/kg was maintained to 48 hr after the single dose administration. For sessions run after administration of the individualized Best Dose of IDRA 21, task accuracy for Long delay (most difficult) trials was increased by 34% of vehicle. Animals were randomly assigned fixed doses of IDRA 21 to determine whether the positive mnemonic response could be maintained. The repeated doses were separated by 3 days, thus allowing for potential cumulative effects. IDRA 21 produced a gradual increase in task accuracy that was maintained on average above vehicle performance levels over an intermittent dosing schedule during a total period of 3 weeks. A separate group of aged monkeys (>20 y) were, as a group, impaired (during vehicle testing) in DMTS performance efficiency relative to the young cohort. IDRA 21 also improved task accuracy by aged rhesus monkeys over the same dose range, but the responses were not as robust as those exhibited by young animals. Aged subjects also appeared to be more individually sensitive to drug dose, and they exhibited shorter task latencies than did the young group. Despite these differences, when the individualized Best Doses were considered, IDRA 21 produced a robust increase in DMTS accuracy of up to 18% of vehicle for trials associated with Medium delay intervals. For both study groups, no obvious untoward effects of IDRA 21 were noted. These findings support the use of AMPA modulators like IDRA 21 in the treatment of cognitive/memory disorders, including those associated with aging. They also indicate that the drug is associated with long-term effects that could limit dosing regimens to one dose every two or three days. The nature of the protracted mnemonic effects produced by the compound remains to be elucidated.
Buccafusco
Jerry J
JJ
Alzheimer's Research Center, Medical College of Georgia, Augusta, GA 30912, USA. jbuccafu@mail.mcg.edu
Weiser
Thomas
T
Winter
Karin
K
Klinder
Klaus
K
Terry
Alvin V
AV
D000375:Aging / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D001581:Benzothiadiazines / Q000494:pharmacology*; D002460:Cell Line; D002755:Choice Behavior / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D007668:Kidney; D008253:Macaca mulatta; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects*; D011897:Random Allocation; D011930:Reaction Time / Q000187:drug effects; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection / Q000379:methods
D001581:Benzothiadiazines; D018698:Glutamic Acid; D018091:Receptors, AMPA; C091420:IDRA 21; C104722:glutamate receptor ionotropic, AMPA 2