Methylphenidate Hydrochloride

Methylphenidate (MPH) has been shown to act as a norepinephrine and dopamine reuptake inhibitor (NDRI), thereby increasing the presence of these neurotransmitters in the space outside the neurons and prolonging their action. Psychostimulants show a dose-related effect on receptor stimulation: higher doses increase norepinephrine (NE) and dopamine (DA) efflux throughout the brain, which can impair cognition and produce locomotor-activating effects. Low doses, by contrast, selectively activate NE and DA neurotransmission within the prefrontal cortex, an area of the brain thought to play a prominent role in ADHD pathophysiology, thereby improving clinical efficacy while limiting side effects. The lower doses used to treat ADHD are not associated with the locomotor-activating effects seen at higher doses; instead, they reduce movement and impulsivity and increase cognitive function, including sustained attention and working memory. Methylphenidate's beneficial effects on sustained attention also appear to be mediated by alpha-1 adrenergic receptor activity.

Clinical findings show that children with ADHD have an abnormality in the dopamine transporter gene (DAT1), the D4 receptor gene (DRD4), and/or the D2 receptor gene, which may be at least partly overcome by methylphenidate's dopaminergic effects, suggesting a possible mode of action.