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

A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency

“…Although the neuropathology of the brain was corrected in only some regions, we were able to achieve correction of hyperactive behaviour and working memory in AAV-TT treated mice over AAV9 treated mice. It is unclear which brain area is responsible for hyperactivity in MPS, however, the frontostriatal pathway has been implicated in ADHD ( Cubillo et al , 2012 ), as it is involved in control of impulsivity, locomotion, affect, attention and emotion ( Takamatsu et al , 2015 ). This pathway connects the cortex, striatum and thalamus ( Morris et al , 2016 ), areas in which we have observed improvement in LAMP2, GFAP and ILB4 levels with AAV-TT treatment.…”

Dopamine transporter mutant animals: a translational perspective

“…In DAT-KO mice it showed its ability to reduce spontaneous hyperactivity (Gainetdinov et al, 1999b) and increase the extracellular level of DA in the prefrontal cortex, but not in the striatum (Takamatsu et al, 2015). Rewarding properties of MPH are also preserved in DAT-KO mice in conditional place preference test (Sora et al, 1998).…”

“…In the water maze, following haloperidol administration, DAT-KOs became as successful as WT mice in finding the platform, and their performance markedly improved with training (Morice et al, 2007). Finally, DAT-KO mice showed impairment of avoidance behavior in shuttle box, which could be reversed by methylphenidate (Takamatsu et al, 2015). …”

Light/dark phase-dependent spontaneous activity is maintained in dopamine-deficient mice

“…The blockade of dopaminergic neurotransmission with dopamine receptor antagonists also results in motor impairment [ 8 ]. In contrast, dopamine transporter knockout mice, which have high levels of dopamine, exhibit hyperactivity [ 9 ]. Based on these observations, dopamine concentrations may be correlated with the extent of locomotor activity.…”