Abstract
Aged-related declines in cognition, especially working memory and executive function, begin in middle-age and these abilities are known to be mediated by the prefrontal cortex (PFC) and more specifically the dopamine (DA) system within the PFC. In both humans and monkeys, there is significant evidence that the PFC is the first cortical region to change with age and the PFC appears to be particularly vulnerable to age-related loss of dopamine (DA). Therefore, the DA system is a strong candidate for therapeutic intervention to slow or reverse age related declines in cognition. In the present study, we administered a novel selective, potent, non-catechol DA D1 R agonist PF-6294 (Pfizer, Inc.) to aged female rhesus monkeys and assessed their performance on two benchmark tasks of working memory – the Delayed Non-match to Sample Task (DNMS) and Delayed Recognition Span Task (DRST). The DNMS task was administered first with the standard 10 s delay and then with 5 min delays, with and without distractors. The DRST was administered each day with four trials with unique sequences and one trial of a repeated sequence to assess evidence learning and retention. Overall, there was no significant effect of drug on performance on any aspect of the DNMS task. In contrast, we demonstrated that a middle range dose of PF-6294 significantly increased memory span on the DRST on the first and last days of testing and by the last day of testing the increased memory span was driven by the performance on the repeated trials.
Highlights
Age-related decline in working memory and executive function have been well documented in both humans and monkeys (Moore et al, 2003, 2006; Alexander et al, 2012; Bizon et al, 2012; Murman, 2015; Salthouse, 2016)
Working memory and executive function are mediated by the prefrontal cortex (PFC) and through the normal function of the dopamine (DA)
There is a significant decrease in DA levels with age (Sawaguchi et al, 1990; Sawaguchi and Goldman-Rakic, 1991; Arnsten et al, 1994; Thierry et al, 1998; Volkow et al, 1998, 2000) and the PFC appears to be vulnerable to age-related loss of dopamine with a 56% decrease in DA neurotransmitter concentration in monkeys 18 years and older (Goldman-Rakic and Brown, 1981; Arnsten et al, 1994)
Summary
Age-related decline in working memory and executive function have been well documented in both humans and monkeys (Moore et al, 2003, 2006; Alexander et al, 2012; Bizon et al, 2012; Murman, 2015; Salthouse, 2016). Evidence from PET scans have shown an age-related decline in DA receptor densities in the striatum and frontal cortex of the aging brain (Bäckman et al, 2011; Karlsson et al, 2011; Rieckmann et al, 2011) and concentrations of D1 receptors are related to performance on tasks of working memory and executive function in middle-age and aged humans and monkeys (Arnsten et al, 1994, 1995; Cai and Arnsten, 1997; Müller et al, 1998; Castner and Goldman-Rakic, 2004; Moore et al, 2005; Bäckman et al, 2011; Rieckmann et al, 2011). It has been demonstrated that administration of DA agonists to aged monkeys improves working memory (Cai and Arnsten, 1997; Castner and Goldman-Rakic, 2004) while administration of DA antagonists decreases performance on working memory tasks (Fischer et al, 2010)
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