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Mechanism of Action of Stimulants in Attention-Deficit/Hyperactivity Disorder

Stephen M. Stahl, MD, PhD

Published: January 15, 2010

Mechanism of Action of Stimulants in Attention-Deficit/Hyperactivity Disorder

Issue: Stimulants hypothetically increase the availability of both dopamine and norepinephrine in prefrontal cortex, which enhances the efficiency of information processing at pyramidal neurons, resulting in the improvement of symptoms in attention-deficit/hyperactivity disorder (ADHD).

Take-Home Points

  • Stimulants have long been known to increase dopamine (DA) in the prefrontal cortex (PFC).
  • It is generally less well appreciated that stimulants also increase norepinephrine (NE).
  • Symptoms of ADHD are theoretically linked to inefficient information processing by pyramidal neurons in PFC, perhaps due in part to imbalances in the neurotransmitters DA and NE.
  • Stimulants such as methylphenidate and amphetamine hypothetically act at these pyramidal neurons to enhance signal strength by increasing NE and to reduce noise by increasing DA, thereby reducing symptoms of inattention, hyperactivity, and impulsivity in ADHD.
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1. Arnsten AFT. Catecholamine and second messenger influences on prefrontal cortical networks of "representational knowledge": a rational bridge between genetics and the symptoms of mental illness. Cereb Cortex. 2007;17(suppl 1):i6-i15. PubMed doi:10.1093/cercor/bhm033

2. Ramos BP, Arnsten AFT. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther. 2007;113(3):523-536. PubMed doi:10.1016/j.pharmthera.2006.11.006

3. Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008.

4. Stahl SM, Mignon L. Stahl’s Illustrated: Attention Deficit Hyperactivity Disorder. New York, NY: Cambridge University Press; 2009.

5. Stahl SM. The prefrontal cortex is out of tune in attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2009;70(7):950-951. PubMed doi:10.4088/JCP.09bs05416

6. Stahl SM. Norepinephrine and dopamine regulate signals and noise in the prefrontal cortex. J Clin Psychiatry. 2009;70(5):617-618. PubMed doi:10.4088/JCP.09bs05143

7. Vijayraghavan S, Wang M, Birnbaum SG, et al. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 2007;10(3):376-384. PubMed doi:10.1038/nn1846

8. Goldman-Rakic PS, Cools AR, Srivastava K. The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive. Phil Trans R Soc Lond. 1996;351(1346):1445-1453. doi:10.1098/rstb.1996.0129

Brainstorms is a section of The Journal of Clinical Psychiatry aimed at providing updates of novel concepts emerging from the neurosciences that have relevance to the practicing psychiatrist.

From the Neuroscience Education Institute in Carlsbad, California, and the Department of Psychiatry at the University of California San Diego, and the Department of Psychiatry at the University of Cambridge, Cambridge, United Kingdom.

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