Guanfacine Hydrochloride

Guanfacine hydrochloride acts as a selective norepinephrine α2A-adrenoceptor agonist to improve prefrontal cortical functions including working memory, attention regulation and impulse control. The mechanism involves activation of postsynaptic α2A-adrenoceptors located on dendritic spines of prefrontal cortex pyramidal neurons. This activation inhibits cAMP-PKA signaling and prevents the opening of nearby potassium channels, thereby strengthening synaptic connectivity and enhancing prefrontal cortex neuronal firing. By protecting NMDAR synapses from excessive cAMP-PKA-K+ channel signaling that occurs during stress, guanfacine maintains the persistent firing of prefrontal cortical networks required for higher cognitive functions. Although beneficial effects are present in rodents, the therapeutic actions are especially evident in primates where the prefrontal cortex has greatly expanded. Beyond prefrontal actions, guanfacine also weakens plasticity in the amygdala, reduces norepinephrine release from the locus coeruleus, and produces anti-inflammatory effects by deactivating microglia.

Fig. 1 Mechanism of action of Guanfacine. (Arnsten A F T. 2020)