Dissociative Effects of Methylphenidate in Nonhuman Primates: Trade-offs between Cognitive and Behavioral Performance

Abstract

Low doses of methylphenidate reduce hyperactivity and improve attention in individuals with attention deficit hyperactivity disorder (ADHD) as well as in healthy humans and animals. Despite its extensive use, relatively little is known about its mechanisms of action. This study investigated the effects of methylphenidate on working memory performance, impulsivity, response accuracy and precision, and the ability to stay on task in rhesus monkeys using an oculomotor delayed response task. Methylphenidate affected task performance in an inverted-U manner in all three subjects tested. The improvements resulted from a reduction in premature responses and, importantly, not from improvement in the memory of target location. The length of time subjects participated in each session was also affected dose dependently. However, the dose at which the length of participation was maximally increased significantly impaired performance on the working memory task. This dissociation of effects has implications for the treatment of ADHD, for the non-prescription use of methylphenidate for cognitive enhancement, and for furthering the basic understanding of the neural substrate underlying these processes.

Methylphenidate does not enhance visual working memory but benefits motivation in macaque monkeys

“…Lastly, we also noticed that monkey M performed particularly longer sessions following treatment. This observation is in line with that of Rajala et al (2012), however, that measure largely depends on satiety, which itself depends on several non-experimental factors more difficult to control. Nevertheless, we computed the total number of trials performed by each animal and tested whether these were significantly larger in treatment versus corresponding control sessions.…”

“…Conversely, more recent studies have reported enhancing effects of MPH on delayed response (Gamo et al, 2010;Rajala et al, 2012) and DMTS performance (Bain et al, 2003; but see Soto et al, 2013 as well as Hutsell andBanks, 2015). However, best-dose analyses-as used in Gamo et al (2010)-are prone to false positives (Soto et al, 2013).…”

“…These additional doses were 0.13, 0.18, 0.25, 0.35, 0.7, and 1.7 mg/kg. Previous non-human primate research mostly investigated doses ranging from 0.1 to 1 mg/kg (Bartus, 1979;Bain et al, 2003;Gamo et al, 2010;Hutsell and Banks, 2015), although both smaller (0.01-0.3 mg/kg; Soto et al, 2013) and higher doses (1.5-9 mg/kg; Rajala et al, 2012) have recently been tested. None of the three monkeys in this study had received any MPH prior to the experiments, and each animal received its respective MPH doses only once.…”

“…To fully establish a link between catecholamines and working memory performance, it is critical to test whether their effects depend on memory load. For example, studies using the DA and NE reuptake inhibitor methylphenidate (MPH) to manipulate catecholamine M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 3 levels in monkeys have variously reported detrimental effects (Bartus, 1979), no significant effects (Bartus, 1978;Rajala et al, 2012;Soto et al, 2013;Hutsell and Banks, 2015), and enhancing effects on performance in single-memorandum delayed response tasks (Bain et al, 2003;Gamo et al, 2010). One potential reason for such equivocal results is the unaddressed possibility that catecholamine effects are most apparent when tasks are made more difficult by increasing mnemonic demands.…”

Striatal dopamine modulates timing of self-initiated saccades

“…Increased impulsivity might be linked with impaired time perception, such that the promotion of the subjective passage of time may facilitate early impulsive responses (Wittmann and Paulus, 2008;Pine et al, 2010). Recently, correlation between impulsivity and eye movements has been shown in humans (Munoz et al, 2003;Cirilli et al, 2011;Hakvoort Schwerdtfeger et al, 2012) and monkeys (Rajala et al, 2012). In particular, Rajala et al (2014) found that the availability of DA transporter in the basal ganglia correlated with the rate of early saccades in the triggered MS task with a long delay (up to 6 s), suggesting that reduced DA might cause impulsive behavior.…”