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Journal of Neuroscience, Vol 8, 4287-4298, Copyright © 1988 by Society for Neuroscience
The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes
AF Arnsten, JX Cai and PS Goldman-Rakic
Section of Neuroanatomy, Yale Medical School, New Haven, Connecticut 06510.
The present study attempted to identify an alpha-2 agonist that could
improve working memory in aged nonhuman primates without the marked
hypotensive and sedative side effects produced by clonidine. Toward this
end, the hypotensive, sedative, and memory-altering properties of the
alpha-2 adrenergic agonists, B-HT920 and guanfacine, were compared with
clonidine's effects in 9 aged rhesus monkeys. Memory capacity was assessed
by a variable delay, spatial delayed response paradigm that requires the
animal to remember information over short temporal intervals and to update
this information on every trial. B-HT920 was found to produce a
dose-response profile qualitatively similar to, but weaker than, clonidine:
low doses impaired memory and began to lower blood pressure and produce
sedation, while high doses improved memory. In contrast, guanfacine
produced a dose-response profile opposite to that seen with clonidine: low
doses improved memory without inducing hypotension or sedation, while the
memory-impairing, hypotensive, and sedating properties of the drug were
observed at higher doses. The potency of the 3 agonists to lower blood
pressure was clonidine = B- HT920 greater than guanfacine; sedation was
affected in the order clonidine greater than B-HT920 greater than
guanfacine; for memory impairment, as measured by performance on the
delayed response task, the rank order potency was clonidine greater than
B-HT920 greater than guanfacine, while for memory improvement it was
guanfacine greater than clonidine greater than B-HT920. These differences
in rank order potency are consistent with the recent proposal of alpha-2
receptor subtypes, a rauwolscine-sensitive site (Rs) that binds clonidine
greater than B- HT920 greater than guanfacine and a rauwolscine-insensitive
site (Ri) that binds guanfacine greater than clonidine greater than B-HT920
(Boyajian and Leslie, 1987). The data suggest that the hypotensive,
sedating, and memory-impairing effects of alpha-2 agonists may be due to
actions at one subtype of receptor (Rs), while the memory-enhancing effects
of these drugs may result from actions at another alpha-2 receptor subtype,
the Ri site. The ability of low doses of guanfacine to improve memory
without inducing hypotension or sedation indicates that this agonist may be
an excellent candidate for treating memory disorders in man.
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