Enhancement of working memory in aged monkeys by a sensitizing regimen of dopamine D1 receptor stimulation

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 D-1 receptor signaling has been implicated in age-related cognitive decline. Here, we report that an intermittent, sensitizing regimen of the D-1 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 D-1 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 D-1 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.