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Brainstorms

Mechanism of Action of α2A-Adrenergic Agonists in Attention-Deficit/Hyperactivity Disorder With or Without Oppositional Symptoms

Stephen M. Stahl, MD, PhD

Published: March 15, 2010

Mechanism of Action of α2A-Adrenergic Agonists in Attention-Deficit/Hyperactivity Disorder With or Without Oppositional Symptoms

Issue: α2A-Adrenergic agonists hypothetically increase the strength of signals in prefrontal cortex (PFC), enhancing the efficiency of information processing at pyramidal neurons and resulting in the improvement of symptoms in attention-deficit/hyperactivity disorder (ADHD), including oppositional symptoms.

Take-Home Points

  • A novel nonstimulant medication, guanfacine XR acts selectively at α2A-adrenergic receptors.
  • Stimulation of α2A receptors enhances key signal inputs to pyramidal neurons in prefrontal cortex.
  • Theoretically, enhancing key glutamate signals can reduce not only classical ADHD symptoms, such as hyperactivity, inattention, and impulsivity, but also oppositional symptoms.
  • Guanfacine XR is an approved first-line treatment for classical ADHD symptoms and may also prove to be useful as an augmenting agent to stimulants for treatment-resistant ADHD, including the often difficult to treat oppositional symptoms associated with this disorder.
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References

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, New York: Cambridge University Press; 2008.

4. Stahl SM, Mignon L. Stahl’s Illustrated: Attention Deficit Hyperactivity Disorder. New York, New York: 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. Mechanism of action of stimulants in attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2010;71(1):12-13.

7. 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

8. 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

9. Goldman-Rakic PS. 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.

For reprint and financial disclosure information, go to www.psychiatrist.com/brainstorms.

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