Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder

J Clin Psychopharmacol. 2008 Jun;28(3 Suppl 2):S46-53. doi: 10.1097/JCP.0b013e318173312f.


Stimulants are part of the standard-of-care treatment for attention-deficit/hyperactivity disorder (ADHD). Methylphenidate, with a history of use spanning approximately 5 decades, is a first-line stimulant treatment for ADHD. Methylphenidate chiefly affects the prefrontal cortex and striatum, the mechanism of action being modulation of catecholaminergic tone. Methylphenidate treatment produces an increase in dopamine (DA) signaling through multiple actions, including blockade of the DA reuptake transporter and amplification of DA response duration, disinhibition of DA D2 autoreceptors and amplification of DA tone, and activation of D1 receptors on the postsynaptic neuron. The actions of methylphenidate may also be mediated by stimulation of the noradrenergic alpha2 receptor and DA D1 receptor in the cortex. The role of other neurotransmitters such as histamine, acetylcholine, serotonin, and alpha-agonists in modulating catecholamine pathophysiology in ADHD and ADHD treatment needs to be elucidated. Overall, the changes in catecholaminergic tone clinically manifest as improvements in attention deficit, distractibility, and motor hyperactivity in patients with ADHD.

Publication types

  • Review

MeSH terms

  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / physiopathology
  • Central Nervous System Stimulants / therapeutic use*
  • Child
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiopathology
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / drug effects
  • Dopamine Plasma Membrane Transport Proteins / physiology
  • Humans
  • Methylphenidate / therapeutic use*
  • Nerve Net / drug effects
  • Nerve Net / physiopathology
  • Norepinephrine / metabolism*
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiopathology
  • Receptors, Adrenergic, alpha-2 / drug effects
  • Receptors, Adrenergic, alpha-2 / physiology
  • Receptors, Dopamine D1 / drug effects
  • Receptors, Dopamine D1 / physiology
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology


  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Receptors, Adrenergic, alpha-2
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Methylphenidate
  • Dopamine
  • Norepinephrine