Title:Improvement of Learning and Increase in Dopamine Level in the Frontal Cortex by Methylphenidate in Mice Lacking Dopamine Transporter
VOLUME: 15 ISSUE: 3
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
Affiliation:Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
Keywords:ADHD, dopamine transporter, frontal cortex, knockout, learning, methylphenidate, norepinephrine
transporter.
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.
