Why is methylphenidate effective in ADHD

Abstract

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent neurobehavioral disorders. Methylphenidate (MPH) is a psychostimulant widely used for the treatment of ADHD. MPH is an inhibitor of dopamine transporter (DAT), and increases dopamine (DA) levels by inhibiting dopamine uptakes in patient brains. On the other hand, the involvement of NMDA type glutamate receptors (NMDARs) in the pathogenesis of ADHD has been also postulated. Magnetic resonance spectroscopy (MRS) study showed a decrease of combined glutamate/glutamine to creatinine ratio in the right anterior cingulated cortex in ADHD adults. In addition, a NMDA subunit gene polymorphism (GRIN2B rs2284411) has been reported to be an important predictor of MPH response in ADHD. Taken together, NMDAR functions are somehow disturbed in ADHD. However, the relationship between the increment of dopamine levels and the improvement of NMDAR functions is largely unknown. Recently, Shibasaki et al. have reported that DA Journal of Brain Science, January 25, 2018,Vol.48 6 causes a functional reversal of glycine transporter 1 (GlyT1), causing astrocytes to release glycine. Glycine is a very important co-agonist for NMDARs and plays a role in treating ADHD by modulating the glutamatergic neurotransmission system through activating NMDARs. Thus, I postulate the following hypothesis. MPH blocks DAT and increases dopamine levels. The increment of dopamine levels activates astrocyte to release glycine. The increment of glycine levels improves NMDAR functions, resulting in improvement of ADHD. Key wards: ADHD, dopamine, glycine, glycine transporter