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
*****sed by a variable delay, spatial delayed response paradigm that
requires the animal to remember information over short tem****al
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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