Ventral striatum supports Methylphenidate therapeutic effects on impulsive choices expressed in temporal discounting task - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Scientific Reports Année : 2020

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

Résumé

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. 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. Delay discounting paradigms are designed using the concept of temporal discounting, based on the observation that humans and animals devaluate future outcomes 5. Impulsive choices, which derive from high discounting, are a central aspect of ADHD and delay aversion is considered as an important component in the development of this pathology 6,7. MPH, the primary medication used to treat ADHD, significantly improves the behavioural symptoms associated with ADHD 8. Specifically, MPH decreases impulsive choices in ADHD patients performing DDT, in which they have to choose between an SIR and an LDR 9-11 and also reduces discounting in healthy humans 12 , rodents 13 and monkeys 14. The efficacy of this treatment depends on the dose. Slezak et al., have shown that trial omissions increased along with dose in rats 15 and the same effect has been reported in monkeys that became drowsy at high doses and were inconsistent in performing the task 16. According to literature review conducted by Konrad-Bindl, et al. (2016), drowsiness is the most commonly recorded side effect in humans (found in up to 32% of patients) 17. Thus, dosage of this dopaminergic agent is a central element to be considered. At the pharmacological level, MPH blocks dopamine reuptake, enhancing dopamine signalling in the cortico-striatal circuitry 11,16,18. However, the mechanisms and specific sites behind its therapeutic effects remain
Fichier principal
Vignette du fichier
Martinez et al. Scient. report (2020).pdf (1.86 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03084754 , version 1 (21-12-2020)

Identifiants

Citer

Eva Martinez, Benjamin Pasquereau, Guillaume Drui, Yosuke Saga, Élise Météreau, et al.. Ventral striatum supports Methylphenidate therapeutic effects on impulsive choices expressed in temporal discounting task. Scientific Reports, 2020, 10 (1), ⟨10.1038/s41598-020-57595-6⟩. ⟨hal-03084754⟩
55 Consultations
35 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More