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The Journal of Neuroscience, February 11, 2004, 24(6):1446-1450; doi:10.1523/JNEUROSCI.3987-03.2004

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Behavioral/Systems/Cognitive
Enhancement of Working Memory in Aged Monkeys by a Sensitizing Regimen of Dopamine D₁ Receptor Stimulation

Stacy A. Castner^2,3 and Patricia S. Goldman-Rakic¹ 

¹Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, ²MIICRO, Inc., Chicago, Illinois 60607, and ³Departments of Psychiatry and Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois 60612

A natural consequence of aging is a loss of dopamine function and associated deficits in working memory in both human and nonhuman primates. Specifically, deficiency of D₁ receptor signaling has been implicated in age-related cognitive decline. Here, we report that an intermittent, sensitizing regimen of the D₁ dopamine agonist ABT-431 dramatically enhances working memory performance in aged rhesus monkeys, while either producing impairment or having little effect on performance in young adult monkeys. Importantly, cognitive enhancement in the aged monkeys was still evident for >1 year after cessation of D₁ treatment. Because intermittent exposure to low doses of amphetamine and other stimulants has been shown to enhance responsiveness to subsequent stimulant exposure, our findings suggest that sensitization of D₁ signaling may provide a novel neurobiological mechanism for improving a core cognitive process in conditions in which dopamine function has deteriorated, such as in normal aging and Parkinson's disease.

Key words: spatial working memory; nonhuman primate; D₁ agonist; sensitization; aging; D₁ dopamine receptors

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Received Aug 28, 2003; revised November 27, 2003; accepted December 1, 2003.

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