THE EFFECTS OF A NOVEL NON-CATECHOL DOPAMINE PARTIAL AGONIST ON WORKING MEMORY IN THE AGED RHESUS MONKEY

Abstract

Deficient D1 receptor signaling, particularly in the PFC, has been directly implicated in age-related decline in cognitive functions, including memory capacity and flexibility in nonhuman primates (Goldman-Rakic and Brown, 1981) and humans (Ota et al., 2006). Working memory in both aged and experimentally-depleted monkeys are improved by the partial D1 receptor agonist (D1R) SKF38393 (Arnsten et al., 1994). Accordingly, the PFC DA system is a strong target for therapeutic intervention to slow or reverse cognitive decline. In this study, we assess the effect of a novel class of non-catechol D1R agonists with favorable drug-like properties, PF-6294, on the performance of aged female rhesus monkeys in tasks of working memory and executive function. This study was divided into three drug/testing sessions. Each monkey received daily administration of one of three doses (0.0021, 0.021 and 0.24 mg/kg) or a placebo during each of the three sessions. A cross-over design was used and each monkey received two of the three doses and the placebo once during the study. Doses were randomly assigned to each monkey and treatments were administered daily over 3 weeks by subcutaneous injection one hour prior to the testing session which occurred 5 days/week. A six-week wash-out period occurred between each session during which no drug was administered and monkeys were not tested. During each session, we administered 2 tasks: Delayed Non-Matching to Sample (DNMS), with and without delays, and Delayed Recognition Span Task (DRST). No significant effect of treatment was observed in the basic DNMS or delayed version of task. However, the mid-range dose significantly affected DRST performance. Specifically, monkeys administered the 0.021 mg/kg dose achieved a significantly greater span of correct responses than monkeys receiving placebo or other doses both acutely on day 1, and after repeated administration at day 4. These data demonstrate that this new class of non-catechol D1R agonists improves working memory spans in aged monkeys and that this effect is maintained over time. D1R-based pharmacotherapies represent an attractive target for the treatment of cognitive decline associated with neurological disorders and warrant further investigation.