Ventral striatum supports Methylphenidate therapeutic effects on impulsive choices expressed in temporal discounting task

Eva Martinez,Léon Tremblay,Guillaume Drui,Élise Météreau,Yosuke Saga,Benjamin Pasquereau

doi:10.1038/s41598-020-57595-6

Abstract

Methylphenidate (MPH) is a dopamine transporter (DAT) inhibitor used to treat attention-deficit/hyperactivity-disorder (ADHD). ADHD patients make impulsive choices in delay discounting tasks (DDT) and MPH reduces such impulsivity, but its therapeutic site of action remains unknown. Based on the high density of DAT in the striatum, we hypothesized that the striatum, especially the ventral striatum (VS) and caudate nucleus which both encode temporal discounting, can be preferential MPH action sites. To determine whether one of these striatal territories is predominantly involved in the effect of MPH, we trained monkeys to make choices during DDT. First, consistent with clinical observations, we found an overall reduction of impulsive choices with a low dose of MPH administered via intramuscular injections, whereas we reported sedative-like effects with a higher dose. Then, using PET-imaging, we found that the therapeutic reduction of impulsive choices was associated with selective DAT occupancy of MPH in the VS. Finally, we confirmed the selective involvement of the VS in the effect of MPH by testing the animals’ impulsivity with microinjections of the drug in distinct striatal territories. Together, these results show that the therapeutic effect of MPH on impulsive decisions is mainly restricted to its action in the VS.

Highlights

Methylphenidate (Ritalin©, MPH) is dopamine transporter (DAT) inhibitor used as a treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), a highly prevalent, clinically heterogeneous neuropsychiatric disorder characterized by impairing levels of inattention and/or hyperactivity associated with impulsive behaviors[1,2]
To determine individual temporal discounting and impulsive choices, three monkeys were trained to perform the delay discounting tasks (DDT) (Fig. 1A), in which they freely choose between a fixed small immediate rewards (SIR) and LDRs
We found that low-dose MPH reduced the discounting factor on the DDT, while high-dose MPH had adverse effects on the animals, inducing a sharp increase in omissions and making them unable to perform the task

Summary

Introduction

Methylphenidate (Ritalin©, MPH) is dopamine transporter (DAT) inhibitor used as a treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), a highly prevalent, clinically heterogeneous neuropsychiatric disorder characterized by impairing levels of inattention and/or hyperactivity associated with impulsive behaviors[1,2] Among these impulsive behaviours, ADHD patients often make impulsive choices i.e. they choose small immediate rewards (SIR) over larger delayed ones (LDR) more often than healthy control subjects do in delay discounting tasks (DDT)[3,4]. MPH decreases impulsive choices in ADHD patients performing DDT, in which they have to choose between an SIR and an LDR9–11 and reduces discounting in healthy humans[12], rodents[13] and monkeys[14] The efficacy of this treatment depends on the dose. To investigate the specific role of the VS and the CdN in the therapeutic effects of MPH on impulsive choices, micro-injections of MPH were performed directly inside these two structures

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