Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function

Biol Psychiatry. 2006 Nov 15;60(10):1111-20. doi: 10.1016/j.biopsych.2006.04.022. Epub 2006 Jun 23.


Background: Low doses of psychostimulants, such as methylphenidate (MPH), are widely used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Surprisingly little is known about the neural mechanisms that underlie the behavioral/cognitive actions of these drugs. The prefrontal cortex (PFC) is implicated in ADHD. Moreover, dopamine (DA) and norepinephrine (NE) are important modulators of PFC-dependent cognition. To date, the actions of low-dose psychostimulants on PFC DA and NE neurotransmission are unknown.

Methods: In vivo microdialysis was used to compare the effects of low-dose MPH on NE and DA efflux within the PFC and select subcortical fields in male rats. Doses used (oral, 2.0 mg/kg; intraperitoneal, .25-1.0 mg/kg) were first determined to produce clinically relevant plasma concentrations and to facilitate both PFC-dependent attention and working memory.

Results: At low doses that improve PFC-dependent cognitive function and that are devoid of locomotor-activating effects, MPH substantially increases NE and DA efflux within the PFC. In contrast, outside the PFC these doses of MPH have minimal impact on NE and DA efflux.

Conclusions: The current observations suggest that the therapeutic actions of low-dose psychostimulants involve the preferential activation of catecholamine neurotransmission within the PFC.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic Uptake Inhibitors / blood
  • Adrenergic Uptake Inhibitors / pharmacology*
  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • Brain Chemistry / drug effects*
  • Catecholamines / metabolism*
  • Chromatography, High Pressure Liquid / methods
  • Cognition / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Administration Routes
  • Electroencephalography / methods
  • Electromyography / methods
  • Male
  • Memory, Short-Term / drug effects
  • Methylphenidate / blood
  • Methylphenidate / pharmacology*
  • Microdialysis / methods
  • Motor Activity / drug effects
  • Prefrontal Cortex / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Detection, Psychological / drug effects
  • Sleep / drug effects
  • Vision, Ocular / drug effects


  • Adrenergic Uptake Inhibitors
  • Catecholamines
  • Methylphenidate