Negligible Effects of Acute Atomoxetine Administration on Visual Working Memory in the Macaque Monkey

Abstract

Working memory (WM) is a basic cognitive process central to daily activities including communication and problem solving. This limited capacity system guides future behaviour through the short-term retention of information. The neural basis of WM is thought to lie in the persistent activity of a network of prefrontal cortical neurons. This activity presents itself during the retention interval of behavioural tasks that probe WM and is reported to be influenced by catecholamines. Accordingly, catecholamine reuptake transporter inhibitors enhance neurotransmission of catecholamines and thus, are said to modulate WM performance. Atomoxetine (ATX) selectively inhibits the reuptake of dopamine and norepinephrine. Evidence of acute ATX effects on WM performance in healthy nonhuman primates or humans is currently lacking. Reports of ATX-induced improvements are equivocal because the majority of studies are sub chronic and the implemented tasks are often inadequate in their measure of WM. Here we tested the acute effects of orally administered ATX on the performance of two female rhesus macaques in a delayed visual sequential comparison (VSC) task with a wide range of doses (0.03 – 3.0 mg/kg). This task reliably assesses both the limited capacity and short time interval of WM by implementing a memory load greater than 2 and a 1s retention interval. It is hypothesized that ATX improves WM performance on the delayed VSC task in a dose- and memory load-dependent manner. Despite the reported contribution of catecholamines on cognition, there were no dose- or memory load-dependent effects observed on delayed VSC task performance following systemic ATX administration. In fact, all changes in performance were within the variability of the control data. While the findings failed to establish a role for catecholamines in WM, a potential modulatory role in motivation was revealed. An increase in task engagement was observed on the task, prompting the implementation of a visual progressive ratio task to further assess the potential motivational effects. These results reveal the need to re-evaluate the notion that catecholamines are capable of modulating WM and direct our attention to their contribution to motivation.