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Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Improvement of Learning and Increase in Dopamine Level in the Frontal Cortex by Methylphenidate in Mice Lacking Dopamine Transporter

Author(s): Y. Takamatsu, Y. Hagino, A. Sato, T. Takahashi, S.Y. Nagasawa, Y. Kubo, M. Mizuguchi, G.R. Uhl, I. Sora and K. Ikeda

Volume 15, Issue 3, 2015

Page: [245 - 252] Pages: 8

DOI: 10.2174/1566524015666150330144018

open access plus

Abstract

The symptoms of attention-deficit/hyperactivity disorder (ADHD) are characterized by inattention and hyperactivity-impulsivity. It is a common childhood neurodevelopmental disorder that often persists into adulthood. Improvements in ADHD symptoms using psychostimulants have been recognized as a paradoxical calming effect. The psychostimulant methylphenidate (MPH) is currently used as the first-line medication for the management of ADHD. Recent studies have drawn attention to altered dopamine-mediated neurotransmission in ADHD, particularly reuptake by the dopamine transporter (DAT). This hypothesis is supported by the observation that DAT knockout mice exhibit marked hyperactivity that is responsive to acute MPH treatment. However, other behaviors relevant to ADHD have not been fully clarified. In the present study, we observed learning impairment in shuttle-box avoidance behavior together with hyperactivity in a novel environment in DAT knockout mice. Methylphenidate normalized these behaviors and enhanced escape activity in the tail suspension test. Interestingly, the effective dose of MPH increased extracellular dopamine in the prefrontal cortex but not striatum, suggesting an important role for changes in prefrontal dopamine in ADHD. Research that uses rodent models such as DAT knockout mice may be useful for elucidating the pathophysiology of ADHD.

Keywords: ADHD, dopamine transporter, frontal cortex, knockout, learning, methylphenidate, norepinephrine transporter.


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