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The Journal of Neuroscience, April 15, 2009, 29(15):4690-4696; doi:10.1523/JNEUROSCI.3266-08.2009

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

Philip L. Clatworthy,^1,2 Simon J. G. Lewis,¹ Laurent Brichard,^2 * Young T. Hong,^2 * David Izquierdo,^2 * Luke Clark,¹ Roshan Cools,^1,4 Franklin I. Aigbirhio,^1,2 Jean-Claude Baron,^1,2,5 Timothy D. Fryer,^1,2 and Trevor W. Robbins^1,3

¹Behavioural and Clinical Neuroscience Institute, ²Wolfson Brain Imaging Centre, and ³Department of Experimental Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom, ⁴Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen 6500HB, The Netherlands, and ⁵Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge CB2 2QQ, United Kingdom

Correspondence should be addressed to Prof. Trevor W. Robbins, Behavioural and Clinical Neuroscience Institute, Department of Experimental Psychology, University of Cambridge, Downing Site, Cambridge CB2 3EB, UK. Email: twr2{at}cam.ac.uk

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 D₂/D₃ 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 D₂/D₃ receptor availability in postcommissural caudate, measured using [¹¹C]-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.

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Received July 12, 2008; revised Jan. 4, 2009; accepted Feb. 4, 2009.

Correspondence should be addressed to Prof. Trevor W. Robbins, Behavioural and Clinical Neuroscience Institute, Department of Experimental Psychology, University of Cambridge, Downing Site, Cambridge CB2 3EB, UK. Email: twr2{at}cam.ac.uk

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