Dopamine Release in Dissociable Striatal Subregions Predicts the Different Effects of Oral Methylphenidate on Reversal Learning and Spatial Working Memory

Abstract

Previous data suggest that methylphenidate can have variable effects on different cognitive tasks both within and between individuals. This is thought to be underpinned by inverted U-shaped relationships between cognitive performance and dopaminergic activity in relatively separate fronto-striatal circuits and reflected by individual differences in trait impulsivity. Direct evidence for this is currently lacking. In this study, we demonstrate for the first time that therapeutic doses of oral methylphenidate administered to young healthy subjects result in different sized changes in D 2 /D 3 receptor availability in different regions of the human striatum and that the change in receptor availability within an individual subregion predicts cognitive performance on a particular task. Methylphenidate produced significantly different effects on reversal learning and spatial working memory tasks within individuals. Performance on the reversal learning task was predicted by the drug-induced change in D 2 /D 3 receptor availability in postcommissural caudate, measured using [ 11 C]-raclopride radioligand PET imaging, whereas performance on the spatial working memory task was predicted by changes in receptor availability in the ventral striatum. Reversal learning performance was also predicted by subjects' trait impulsivity, such that the most impulsive individuals benefited more from methylphenidate, consistent with this drug's beneficial effects on cognition in attention deficit hyperactivity disorder.

Methylphenidate Effects on Brain Activity as a Function of SLC6A3 Genotype and Striatal Dopamine Transporter Availability

“…We thus build on previous studies (Clatworthy et al, 2009;Cools and D'Esposito, 2011) in attempting to identify predictors of the variability in response to dopaminergic drugs such as MPH, which may help improve our mechanistic understanding of this clinically relevant compound.…”

Neurogenetics and Pharmacology of Learning, Motivation, and Cognition

“…Indeed, dopamine-releasing stimulants are well known to improve cognitive function in both participants with ADHD and healthy individuals (Klorman et al, 1984;Elliott et al, 1997). However, multiple studies have shown that whether dopaminergic agents (particularly D2 receptor agonists), improve or impair cognitive function strongly depends on baseline measures (Kimberg et al, 1998;Mehta et al, 2004;Roesch-Ely et al, 2005;Frank and O'Reilly, 2006;Cools et al, 2009Cools et al, , 2007Clatworthy et al, 2009). For example, D2 stimulation generally improves performance in individuals with low working memory span (Kimberg et al, 1998;Frank and O'Reilly, 2006), or high impulsivity (Cools et al, 2007), or low baseline DA synthesis (Cools et al, 2009), whereas it impairs performance in those in the opposite groups.…”

“…Furthermore, DA drugs can affect the degree to which working memory updating strategies are themselves learned across trials (Frank and O'Reilly, 2006;Moustafa et al, 2008b). Finally, a recent study showed that the extent to which stimulants cognitive function is predicted by drug-induced changes in D2 receptor availability in distinct striatal sub-regions, depending on the task (Clatworthy et al, 2009).…”

The moderating role of the dopamine transporter 1 gene on P50 sensory gating and its modulation by nicotine

“…Observations that dopamine agonists either improve or impair brain processes have been accounted for by using the inverted-U principle, that is, agonists might stimulate the dopamine system to 'optimal' or overdosed levels in individuals with low and high baseline dopamine system functioning, respectively (Cools, 2008;Cools and Robbins, 2004). Initially seen in the context of prefrontal D 1 R receptor stimulation, the inverted-U effect has also been extended to the striatal D 2 R system (Clatworthy et al, 2009;Cools et al, 2009;Phillips et al, 2004). Studies investigating the moderation of dopamine drug effects on brain activity and performance by variables that might index baseline dopamine levels have made use of the genetic variation associated with Taq1A DRD2 gene polymorphisms, and have observed a baselinedependency of dopamine drug effects on reward-related processing (Cohen et al, 2007).…”