Guanfacine for the Treatment of PFC Disorders

Although previous research has often focused on the pre-synaptic actions of a2A-AR, guanfacine strengthens PFC connections by stimulating post-synaptic a2A-AR on dendritic spines in PFC (green arrowheads), which are often located next to the synapse (white double arrowheads). Stimulation of a2A-AR inhibits cAMP-PKA opening of nearby K+ channels, and thus strengthens network firing. Guanfacine improves a variety of PFC functions, especially under distracting conditions when strong PFC function is needed.

If you are interested:

• Arnsten and Jin (2012) Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 85:45-58.
• Kim et al. (2012) Effects of a2A adrenergic receptor agonist on time and risk preference in primates. Psychopharmacology 219: 363-75.
• Arnsten (2010) The use of a2A adrenergic agonists for the treatment of ADHD. Expert Rev Neurother.10:1595-605.
• Wang et al. (2007) Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in PFC. Cell 129: 397-410

The stimulant medications and atomoxetine work in part by blocking NE (and DA) transporters, enhancing endogenous NE and DA stimulation of a2A-AR and D1R. Stimulants such as methylphenidate have greater effects on NE than DA in the PFC, and at low therapeutic doses, their effects in PFC predominate over other brain regions, thus reducing risk of addiction and abuse.

If you are interested:

• Gamo et al. (2010 Methylphenidate and atomoxetine enhance prefrontal function through a2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry. 49: 1011-23.
• Berridge & Devilbiss (2011) Psychostimulants as cognitive enhancers: the prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder. Biol Psychiatry 69 :e101-11.