Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental pathology. Its etiology is unknown but there are multiple genetic and environmental factors of vulnerability related with catecholaminergic, dopamine (DA) and norepinephrine (NE), dysfunction at the central nervous system (CNS) and mainly in the prefrontal cortex (CPF). This dysfunction is the essential target for its pharmacological treatment. In fact, the treatment of ADHD has focused on the use of drugs that act mainly on catecholaminergic presynaptic mechanisms such as psychostimulants: methylphenidate and amphetamine derivatives, or not stimulants agents, such as atomoxetine. Although initially more importance was given to the DA, there are multiple clinical and experimental arguments that support the importance of the NE in the pathophysiology and treatment of ADHD [1,2].
 

Recently the European Medicines Agency (EMA) has approved another not psychostimulant drug, guanfacine extended release, as a new option to the treatment of ADHD, which acts at postsynaptic level. Guanfacine is the more selective agonist alfa2A postsynaptic receptor, so it inhibits the adenylate-cyclase and decreases the production of cAMP [3]. In layer III of the CPF, some of the pyramidal cells are interconnected by NMDA glutamatergic receptors, located in dendritic spines. Glutamate provides the “gross fuel” of the CPF, while alpha2A receptors, modulating excitatory glutamate transmission, improve the connectivity between neurons and coordinate the “signal” to create the working memory and behavioral inhibition, fundamental facts in the CPF function [3,4].
 

In addition, on dendritic spines of pyramidal neurons of the CPF are also localized the cAMP-dependent HCN channels (hyperpolarization-activated cyclic nucleotide gated cation), essentially allowing potassium output, which causes hyperpolarization, reducing interconnections in pyramidal neurons and dispersing the synaptic impulses. Thus, an excessive increase of cAMP levels, for example to an uncontrollable stress, opens HCN channels and impairs the connectivity of the CPF. On the contrary, guanfacine, mimicking the action of the NE on the alpha2A postsynaptic receptors, decrease cAMP levels, close HCN channels and recover the connectivity of pyramidal neurons of PFC, thus improving working memory and attention [4].

 
In the PFC there is another regulatory mechanism to restrict possible excessive impulses by an abrupt increase of NE on alpha2A receptors (e.g. stress or excess of psychostimulants). An excess of NE produces a sudden decrease of cAMP that reduces the activity of the PKA (protein kinase A), which activates the PP1 (protein-phosphatase 1). This phosphatase reduces the activation of excitatory glutamate AMPA receptors that protects the working memory. This dual modulator mechanism has been observed also with guanfacine: low doses close HCN channels and increase the excitatory impulses, but high doses inhibit the activation of AMPA receptors which attenuates the excitation [3,4].
 

In addition, dendritic spines are essential for the normal function of the CPF and more than half of the genes involved in ADHD are related to its integrity. Changes in the dendritic trophism are related with behavior, learning and memory alterations. Guanfacine, acting on alpha2A receptors, promotes growth and maturation of dendritic spines of medial PFC, associated with brain function such as learning and memory [5].

 
Guanfacine, in various clinical and experimental models, improve working memory, regulates attention, cognitive performance and behavior. These actions are independent of a sedative effect [3,4]. Current evidence indicates that guanfacine is an effective treatment option for children and adolescents with ADHD as monotherapy, or as adjunctive treatment to psychostimulants, and its adverse events are typically mild to moderate [6,7].

 
At this moment, the psychostimulant drugs are considered the gold standard therapy for ADHD due to their high efficacy compared with atomoxetine. However, an effective therapy with an alternative mechanism of action is needed for patients who demonstrate absent or incomplete clinical responses or those who cannot tolerate stimulants [6]. In contrast with psychostimulants, that increase DA and NE levels in the PFC, secondary to presynaptic action, guanfacine stimulate in direct and selective form postsynaptic alfa2A receptors on the PFC, mimicking NE. This selective action provides a differential mechanism of action for the ADHD treatment that probably explains its clinical efficacy in monotherapy or adjunctive therapy to psychostimulants, and its tolerability and the increase of action spectrum against this disorder [7].

1. López-Muñoz F, Álamo C, Quintero-Gutiérrez FJ, García-García P (2008) A bibliometric study of international scientific productivity in attention-deficit hyperactivity disorder covering the period 1980-2005. Eur Child Adolesc Psychiatr 17: 381-391. 

2. García-García P, López-Muñoz F, Molina JD, Fischer R, Álamo C (2009) Methylphenidate Extended-Release Capsules: A New Formulation for Attention-Deficit Hyperactivity Disorder. Front Drug Design Discov 4: 228-246.

3. Arnsten AFT, Pliszka SR (2011) Catecholamine Influences on Prefrontal Cortical Function: Relevance to Treatment of Attention Deficit Hyperactivity Disorder and Related Disorders. Pharmacol Biochem Behav 99: 211-216.

4. Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, et al. (2007) Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signalling in prefrontal cortex. Cell 129: 397-410.

5. Ren WW, Liu Y, Li BM (2012) Stimulation of a (2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Mol Cell Neurosci 49: 205-216.

6. Bello NT (2015) Clinical utility of guanfacine extended release in the treatment of ADHD in children and adolescents. Patient Prefer Adherence 9: 877-885.

7. Faraone SV, McBurnett K, Sallee FR, Steeber J, López FA (2013) Guanfacine extended release: a novel treatment for attention-deficit/hyperactivity disorder in children and adolescents. Clin Ther 35: 1778-1793