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Journal of Neuroscience, Vol 15, 3429-3439, Copyright © 1995 by Society for Neuroscience
Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys
AF Arnsten, JX Cai, JC Steere and PS Goldman-Rakic
Section of Neurobiology, Yale Medical School, New Haven, Connecticut 06510-8001, USA.
The D2 dopamine (DA) receptor agonist, quinpirole, was characterized in
young adult monkeys, young reserpine-treated monkeys and aged monkeys to
assess the contribution of DA to age-related loss of prefrontal cortical
(PFC) cognitive function. Monkeys were tested on a delayed response memory
task that depends on the PFC, and a fine motor task that taps the functions
of the motor cortex. In young adult monkeys, low quinpirole doses impaired
performance of the PFC and fine motor tasks, while higher doses improved
memory performance and induced dyskinesias and "hallucinatory-like"
behaviors. The pattern of the quinpirole response in reserpine-treated
monkeys suggested that the impairments in delayed response and fine motor
performance resulted from drug actions at D2 autoreceptors, while the
improvement in delayed response performance, dyskinesias and
"hallucinatory-like" behaviors resulted from actions at postsynaptic
receptors. In aged monkeys, low doses of quinpirole continued to impair
fine motor performance, but lost their ability to impair delayed response
performance. The magnitude of cognitive improvement and the incidence of
"hallucinatory- like" behaviors were also reduced in the aged animals,
suggesting some loss of postsynaptic D2 receptor function. The pattern of
results is consistent with the greater loss of DA from the PFC than from
motor areas in aged monkey brain (Goldman-Rakic and Brown, 1981; Wenk et
al., 1989), and indicates that DA depletion contributes significantly to
age- related cognitive decline.
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