Analysis of alpha-2 adrenergic agonist effects on the delayed nonmatch-to-sample performance of aged rhesus monkeys

Abstract

The administration of alpha-2 adrenergic agonists to aged monkeys has been shown to ameliorate their cognitive deficits on the delayed response (DR) task, a test of spatial working memory (3,5). The present experiment tested whether the alpha-2 agonists, clonidine and guanfacine, would also improve working memory for object feature recognition, as tested by the delayed nonmatch-to-sample (DNMS) task. Five aged monkeys were trained on DNMS and were found to have mild performance deficits comparable to those reported previously for monkeys of similar age (32). However, during the subsequent two years of drug testing, the animals' baseline performance steadily improved, and conditions had to be made progressively more difficult to produce errors in performance. Clonidine and guanfacine significantly altered the DNMS performance of the aged monkeys, but drug-induced improvement was not as robust for DNMS as it was for DR. Clonidine produced a triphasic dose/response curve: Impairment was observed at both very low and high doses, while modest improvement was seen in the middle dose range (average maximal improvement of 21 ± 2.4%). Although improvement could occasionally be replicated for some doses, the clonidine dose/response curves were remarkably inconsistent in the middle dose range. Similarly, doses of guanfacine which had previously produced optimal improvement on the DR task, produced only small but significant improvement in DNMS performance (average improvement of 11 ± 3% for the 0.00011–0.000011 mg/kg dose range). By the end of the drug study, three monkeys were performing well (70–75% correct) with lists of 20 objects and over 400 sec delays, and one monkey performed better than 85% correct with lists of 40 objects and over 800 sec delays. Given the high level of performance of the aged monkeys on the DNMS task, it is unclear whether the weak improvement produced by alpha-2 agonists on the DNMS as compared to the DR task is due to ceiling effects, or rather results from alpha-2 adrenergic mechanisms being more important for spatial working memory than memory for object features. Future experiments utilizing a more difficult object working memory task will be necessary to resolve this issue.