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

Abstract

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.

Figure 1.

Delayed-response performance across baseline, D₁ agonist, and post-D₁ agonist testing periods in aged and young monkeys. The filled triangles represent the average performance of four aged (a-c) and three young (d-f) monkeys on the spatial working memory task for individual test sessions across baseline, D₁ agonist (all five blocks), and post-D₁ agonist testing periods. Both aged (a) and young (d) monkeys maintained ∼70% ± 2% correct baseline performance for a minimum of 20 consecutive test sessions before treatment with the D₁ agonist. Whereas the performance of the aged monkeys (b) significantly improved during repeated D₁ agonist treatment, the performance of the young monkeys (e) remained unchanged or became impaired. During the post-D₁ agonist testing period, the improved performance of the aged monkeys was sustained (c), and the young monkeys' performance returned to baseline (f). The r values in the graphs are based on the mean performance for all four aged or all three young monkeys on given test sessions within each testing period.

Figure 3.

The mean number of errors for aged and young monkeys across delays during baseline, D₁ agonist, and post-D₁ agonist testing periods. Shown are the mean number of errors ± SEM (error bars) for aged (open squares) and young (open circles) monkeys across the five different delays (N ranging from 1 to 10 sec) during baseline (a), D₁ agonist (b), and post-D₁ agonist (c) testing periods. There was a significant effect of delay across all of the conditions for both aged and young monkeys, that is, both groups of monkeys made significantly more errors at longer delays. As a group, aged monkeys made significantly fewer errors than did young monkeys at the lowest delays and compared with their own baseline performance during the D₁ agonist (b) and post-D₁ agonist testing periods (c).

Figure 2.

The percentage of days that delayed-response performance was significantly above baseline during the D₁ agonist period. For young monkeys (a) and aged monkeys (b), the percentage (mean ± SEM) of test sessions in which performance was significantly above baseline for each of the five treatment blocks is shown. On the x-axis, the five D₁ agonist blocks (each block corresponded to 5 d of D₁ treatment and a 2-3 week washout period) are chronologically labeled 1-5. The average performance of the aged monkeys was significantly improved by the fifth D₁ agonist block, whereas, as a group, the young monkeys actually showed a decline in performance, as evidenced by the fact that they performed above baseline on only <20% of test sessions for this block. ^*The performance of the young and aged monkeys differed significantly from one another during the fifth treatment block at an α-level of 0.05, as measured by two-way ANOVA with Scheffe post hoc comparisons. Error bars denote SEM.