Biomedical subjects

A F Arnsten

Publications and source records attributed to A F Arnsten.

4 recordsLinked to original sources

PubMed1992

Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task.

With advancing age, monkeys become impaired on a test of spatial working memory, the delayed response task, and show increased susceptibility to interference from irrelevant stimuli (Bartus and Dean 1979). Alpha-2 adrenergic agonists such as clonidine and guanfacine have been shown to improve the delayed response performance of aged monkeys under standard testing conditions (e.g. Arnsten et al. 1988). The current study examined whether these drugs could protect the delayed response performance of aged monkeys when irrelevant stimuli were presented during the delay intervals. Aged monkeys were tested on the variable delayed response task with short delays to minimize memory demands and optimize performance on control (no interference) sessions. During interference sessions, distractors were presented during the delays on 9 of the 30 trials ("distractor" trials). If the aged monkeys had been pretreated with saline, performance was significantly disrupted by the irrelevant stimuli compared to matched saline control sessions. This impairment was not only evident on the 9 distractor trials, but on the 21 remaining "nondistractor" trials as well. However, if the aged monkeys had been pretreated with clonidine or guanfacine, performance was not impaired on the interference sessions. This beneficial effect of the alpha-2 agonists was most apparent on the nondistractor trials. Guanfacine was able to decrease the harmful effects of distraction without any apparent sedative side effects. Co-administration of the alpha-2 antagonists idazoxan or SKF104078 with clonidine blocked the protective effects of the agonist on delayed response performance, consistent with actions at alpha-2 adrenergic receptors. These findings suggest that alpha-2 agonists improve delayed response performance, at least in part, by helping to protect memory from irrelevant stimulation. Clonidine is already used in the treatment of Attention Deficit Disorder, and the current data suggest that guanfacine may also be useful in this regard.

Adrenergic alpha-Agonists↗

PubMed1991

Behavioral and receptor binding analysis of the alpha 2-adrenergic agonist, 5-bromo-6 [2-imidazoline-2-yl amino] quinoxaline (UK-14304): evidence for cognitive enhancement at an alpha 2-adrenoceptor subtype.

The ability of the alpha 2-agonists clonidine, B-HT920 (6-allyl-2-amino-5,6,7,8-tetrohydro-4H-thiazolo-[4,5-d]-azepine) and guanfacine to improve memory in aged monkeys has been related to their affinity to bind at a proposed rauwolscine-insensitive (Ri) subtype of alpha 2-adrenergic receptor, while their hypotensive and sedating effects have been related to affinity at a rauwolscine-sensitive site (Rs) (Arnsten et al., 1988). The present study examined the alpha 2-agonist UK-14304 (5-bromo-6 [2-imidazoline-2-yl amino] quinoxaline) for its binding characteristics in tissue from the brain of the rat and for its behavioral effects in aged monkeys. The drug UK-14304 was found to have slightly higher affinity for the Ri than the Rs site (Ki values of 138 and 245 nM, respectively), but was not as selective as the alpha 2-agonist guanfacine (Ki values of 23 and 340 nM, respectively). Consistent with this binding profile, very small doses of UK-14304 (0.00017-0.17 micrograms/kg) produced a reliable but modest improvement in memory in the aged monkeys (average improvement of 16.7% +/- 2.6% following an optimal dose). No hypotensive or sedating side effects were observed at these small doses. However, hypotension and sedation emerged rapidly when the dose was raised above 1.7 micrograms/kg and at the largest doses tested (50.0-100.0 micrograms/kg), hypotension was severe (systolic pressure below 70 mm Hg) and the animals were too sedated to complete cognitive testing. The separation between doses that improved memory and those that produced hypotension and sedation was not as great for UK-14304 as it was for guanfacine, consistent with the greater selectivity of guanfacine for the Ri site. These results offer a fourth example whereby the ability of an alpha 2-agonist to improve cognitive function, without side effects, could be related to the relative affinities for the Ri and Rs sites.

Adrenergic alpha-Agonists↗

PubMed1987

Noradrenergic mechanisms in age-related cognitive decline.

The alpha-2 agonist, clonidine, improved spatial working memory performance in 13/13 aged rhesus monkeys with documented memory impairments. The clonidine response was blocked by alpha-2, but not alpha-1 antagonists, and appeared to result from actions at postsynaptic alpha-2 receptors in that area of cortex most critical for spatial working memory, the principal sulcal cortex. The data indicate that noradrenergic mechanisms play an important role in the functioning of the frontal association cortex, and support the rationale for giving alpha-2 agonists to restore this function in Alzheimer's patients with profound norepinephrine loss.

Aging↗

PubMedDate not supplied

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

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).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗