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.

Figure 1.

Striatal ROIs for one representative subject. The top portion of the figure shows a 3D rendering of the striatum; the bottom portion shows a coronal T1-weighted MRI brain slice at the anterior commissure, with ROIs superimposed. Regions are (1) ventral striatum, including nucleus accumbens, ventral caudate, and ventral putamen (green), (2) precommissural dorsal caudate (purple), (3) precommissural dorsal putamen (yellow), (4) postcommissural dorsal putamen (blue), and (5) postcommissural dorsal caudate (red).

Figure 2.

Effect of methylphenidate administration on [¹¹C]-raclopride binding potential for all striatal regions of interest (see Materials and Methods). Ordinate shows the mean percentage difference in BP (Eq. 1) (Materials and Methods) between drug and placebo sessions. Error bars represent 1 SE. pre-comm, Precommissural; post-comm, postcommissural.

Figure 3.

Effects of methylphenidate on reversal learning and SWM. Ordinate shows the Z-score for difference in reversal errors, placebo minus methylphenidate. Abscissa shows the equivalent score for between-search errors in the SWM task. Note the difference in drug effects between tasks in most subjects (top left and bottom right quadrants).

Figure 4.

Left, Scatter plot showing an association between drug-induced reduction in D₂/D₃ receptor availability in postcommissural caudate nucleus, expressed as percentage reduction in [¹¹C]-raclopride binding potential (abscissa) and improvement in reversal performance (reduced errors, ordinate). Middle, Scatter plot showing an association between impulsivity (Barratt Impulsivity Score, abscissa) and improvement in reversal performance (reduced errors, ordinate). Right, Scatter plot showing an association between drug-induced reduction in D₂/D₃ receptor availability in the ventral striatum (abscissa) and improvement in SWM performance (reduced errors, ordinate).