Oral Administration of Methylphenidate (Ritalin) Affects Dopamine Release Differentially Between the Prefrontal Cortex and Striatum: A Microdialysis Study in the Monkey

Abstract

Methylphenidate (MPH; trade name Ritalin) is a widely used drug for the treatment of attention deficit hyperactivity disorder (ADHD)and is often used as a cognitive enhancer. Because MPH increases dopamine (DA) release by blocking the DA transporter in the human striatum, MPH is supposed to work on attention and cognition through a DA increase in the striatum. However, ADHD patients show impaired prefrontal cortex (PFC) function and MPH administration is associated with increased neural activity in the PFC. Although MPH is indicated to increase DA release in the rat PFC, there has been no study to examine MPH-induced DA changes in the human PFC because of technical difficulties associated with the low level of PFC DA receptors. Using the microdialysis technique, we examined the effects of oral administration of MPH on DA release in both the PFC and striatum in the monkey. We also tested the effect of MPH on cognitive task performance. As in human studies, in the striatum, both high and low doses of MPH induced consistent increases in DA release ϳ30 min after their administrations. In the PFC, a consistent increase in DA release was observed 1 h after a high dose, but not low doses, of MPH. Low doses of MPH improved cognitive task performance, but a high dose of MPH made the monkey drowsy. Therefore, low-dose MPH-induced cognitive enhancement is supported by striatum DA increase.

Catecholaminergic modulation of the avoidance of cognitive control

“…We hypothesize, in part based on the work by Cavanagh et al (2014), reviewed above, that our effect of MPH on demand avoidance reflects modulation of striatal dopamine. This concurs with a recent study reporting striatal dopamine increases after administration of a low-dose of MPH (Kodama et al, 2017) and also with our previous finding that the effects of MPH on reward-versus punishmentlearning resembled that of the selective dopamine receptor agent sulpiride, which has selective affinity for D2 receptors that are particularly abundant in the striatum (Janssen et al, 2015;van der Schaaf et al, 2014). Moreover, it is generally consistent with prior work, demonstrating a key role for (striatal) dopamine in physical effort-based choice (Buckholtz et al, 2010;Hosking et al, 2015;Salamone et al, 2016;Wardle, Treadway, Mayo, Zald, & de Wit, 2011), although a recent study failed to observe modulation by the selective dopamine antagonists eticlopride and SCH23390 of the willingness to exert cognitive effort (Hosking et al, 2015).…”

Receptor and circuit mechanisms underlying differential procognitive actions of psychostimulants

“…The PFC and procognitive actions of psychostimulants The current study demonstrates that both sustained attention and working memory depend on multiple nodes of frontostriatal circuitry [8]. This is consistent with the fact that ADHD is associated with frontostriatal dysfunction [37][38][39] and that clinically relevant doses of MPH increase catecholamine signaling broadly within this circuit [5,20]. Nonetheless, only MPH action in the dmPFC, and not the vmPFC, dmSTR, or vmSTR, is sufficient to improve both sustained attention and working memory [8].…”

“…Consistent with this, prior studies demonstrate that, in rats, working memory performance is highly dependent on the dmPFC and the dmSTR as well as the ventromedial striatum (vmSTR; [1,8,19]). Relative to low and clinically relevant doses, higher doses of psychostimulants elicit larger and more uniform elevations in norepinephrine (NE) and dopamine (DA) throughout the brain [5,19,20]. Thus, differences in sensitivity to psychostimulants across cognitive processes may reflect broader actions of higher doses across frontostriatal circuitry.…”

Effects of methylphenidate on reversal learning depend on working memory capacity

“…By analogy, we hypothesize that performance in the current task varies with individual differences in the relative weight on working memory and reinforcement learning strategies, which might well correspond with variation in working memory capacity. Moreover, methylphenidate may act on striatal levels of dopamine, as suggested above, but may also affect frontal functioning, through blockade of noradrenaline transporters in the frontal cortex (Arnsten and Dudley 2005;Berridge et al 2006;Berridge and Devilbiss 2011;Kodama et al 2017;Volkow et al 2001;Volkow et al 2012). The impact of putative direct frontal modulation on working memory functioning may differ between individuals with high versus low baseline working memory capacity, and thus differentially affect the balance between WM and RL strategies.…”