Methylphenidate and atomoxetine enhance prefrontal function through α2-adrenergic and dopamine D1 receptors

J Am Acad Child Adolesc Psychiatry. 2010 Oct;49(10):1011-23. doi: 10.1016/j.jaac.2010.06.015. Epub 2010 Sep 1.


Objective: This study examined the effects of the attention-deficit/hyperactivity disorder treatments, methylphenidate (MPH) and atomoxetine (ATM), on prefrontal cortex (PFC) function in monkeys and explored the receptor mechanisms underlying enhancement of PFC function at the behavioral and cellular levels.

Method: Monkeys performed a working memory task after administration of a wide range of MPH or ATM doses. The optimal doses were challenged with the α(2)-adrenoceptor antagonist, idazoxan, or the D(1) dopamine receptor antagonist, SCH23390 (SCH). In a parallel physiology study, neurons were recorded from the dorsolateral PFC of a monkey performing a working memory task. ATM, SCH, or the α(2) antagonist, yohimbine, were applied to the neurons by iontophoresis.

Results: MPH and ATM generally produced inverted-U dose-response curves, with improvement occurring at moderate doses, but not at higher doses. The beneficial effects of these drugs were blocked by idazoxan or SCH. At the cellular level, ATM produced an inverted-U dose-response effect on memory-related firing, enhancing firing for preferred directions (increasing "signals") and decreasing firing for the nonpreferred directions (decreasing "noise"). The increase in persistent firing for the preferred direction was blocked by yohimbine, whereas the suppression of firing for the nonpreferred directions was blocked by SCH.

Conclusions: Optimal doses of MPH or ATM improved PFC cognitive function in monkeys. These enhancing effects appeared to involve indirect stimulation of α(2) adrenoceptors and D(1) dopamine receptors in the PFC. These receptor actions likely contribute to their therapeutic effects in the treatment of attention-deficit/hyperactivity disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / therapeutic use*
  • Animals
  • Appetitive Behavior / drug effects
  • Atomoxetine Hydrochloride
  • Attention Deficit Disorder with Hyperactivity / drug therapy
  • Attention Deficit Disorder with Hyperactivity / psychology
  • Brain Mapping
  • Central Nervous System Stimulants / therapeutic use*
  • Child
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Macaca mulatta
  • Male
  • Memory, Short-Term / drug effects
  • Methylphenidate / therapeutic use*
  • Nerve Net / drug effects
  • Orientation / drug effects
  • Prefrontal Cortex / drug effects
  • Propylamines / therapeutic use*
  • Pyramidal Cells / drug effects
  • Receptors, Adrenergic, alpha-2 / drug effects*
  • Receptors, Dopamine D1 / drug effects*
  • Saccades / drug effects


  • Adrenergic Uptake Inhibitors
  • Central Nervous System Stimulants
  • Propylamines
  • Receptors, Adrenergic, alpha-2
  • Receptors, Dopamine D1
  • Methylphenidate
  • Atomoxetine Hydrochloride