Guanfacine's mechanism of action in treating prefrontal cortical disorders: Successful translation across species

Abstract

The selective norepinephrine (NE) α2A-adrenoceptor (α2A-AR) agonist, guanfacine (Intuniv™), is FDA-approved for treating Attention Deficit Hyperactivity Disorder (ADHD) based on research in animals, a translational success story. Guanfacine is also widely used off-label in additional mental disorders that involve impaired functioning of the prefrontal cortex (PFC), including stress-related disorders such as substance abuse, schizotypic cognitive deficits, and traumatic brain injury. The PFC subserves high order cognitive and executive functions including working memory, abstract reasoning, insight and judgment, and top-down control of attention, action and emotion. These abilities arise from PFC microcircuits with extensive recurrent excitation through NMDAR synapses. There is powerful modulation of these synapses, where cAMP-PKA opening of nearby potassium (K⁺) channels can rapidly and dynamically alter synaptic strength to coordinate arousal state with cognitive state, e.g. to take PFC "offline" during uncontrollable stress. A variety of evidence shows that guanfacine acts within the PFC via post-synaptic α2A-AR on dendritic spines to inhibit cAMP-PKA-K⁺ channel signaling, thus strengthening network connectivity, enhancing PFC neuronal firing, and improving PFC cognitive functions. Although guanfacine's beneficial effects are present in rodent, they are especially evident in primates, where the PFC greatly expands and differentiates. In addition to therapeutic actions in PFC, stress-related disorders may also benefit from additional α2-AR actions, such as weakening plasticity in the amygdala, reducing NE release, and anti-inflammatory actions by deactivating microglia. Altogether, these NE α2-AR actions optimize top-down control by PFC networks, which may explain guanfacine's benefits in a variety of mental disorders.

Keywords: ADHD; Intuniv; Norepinephrine; Schizophrenia; Working memory; α2A-adrenoceptor.

Graphical abstract

Fig. 1

(A) Schematic illustrations of the higher cognitive functions of the prefrontal cortex (PFC). (B) A list of disorders with impaired PFC functioning.

Fig. 2

Spatial working memory circuits of the dlPFC. (A) The oculomotor delayed response (ODR) test of spatial working memory often used to probe the physiological functioning of the dlPFC in monkeys. (B) An example of a dlPFC Delay cell with spatially tuned, persistent firing across the delay period for the neuron’s preferred direction (90°) but little firing for other spatial positions. (C) The microcircuits in deep layer III dlPFC that are thought to underlie spatial working memory. Persistent firing arises from extensive recurrent excitation, where pyramidal cells with shared preferred directions excite each other to keep information “in mind” over the delay period. Spatial tuning is refined by lateral inhibition from parvalbumin-containing GABAergic interneurons, i.e. basket and chandelier cells. (D) Recurrent excitation on spines depends on glutamate stimulation of NMDAR, with surprisingly little contribution from AMPAR. Instead, the permissive effects of AMPAR to depolarize the synaptic membrane and eject magnesium from the NMDAR pore appear to be performed by acetylcholine, including nic-α7R that reside within and near the glutamate synapse. As acetylcholine is released according to arousal state, effective neurotransmission in the dlPFC depends on arousal conditions.

Fig. 3

cAMP-PKA actions in classic circuits vs. dlPFC. (A) In classic circuits, cAMP-PKA signaling in spines enhances plasticity, e.g. via activation of CREB, and PDE4 inhibition improves learning and memory. (B) cAMP-PKA signaling also has classic actions at pre-synaptic sites, e.g. enhancing glutamate release, as occurs in monkey primary visual cortex V1. C. In layer III dlPFC spines, cAMP-PKA signaling opens nearby K⁺ channels (e.g. KCNQ2) to reduce firing. Thus, PDE4 inhibition can be harmful in these circuits.

Fig. 4

Catecholamine actions in dlPFC during optimal vs. stressful arousal conditions. (A) Under optimal arousal conditions (safe, alert, interested), there are moderate levels of NE release that engage high affinity α2A-AR which inhibit feedforward, Ca²⁺-cAMP-PKA-K⁺ signaling to strengthen connectivity and enhance neuronal firing. (B) Under conditions of uncontrollable stress, high levels of catecholamines are released in PFC. High levels of NE engage lower affinity α1-AR, and high levels of dopamine release engage D1R, both of which drive feedforward Ca²⁺-cAMP-PKA-K⁺ signaling to weaken connectivity and reduce neuronal firing.

Fig. 5

Guanfacine’s mechanism of action in the primate dlPFC. (A) A schematic drawing showing how guanfacine stimulation of α2A-AR on dlPFC dendritic spines inhibits cAMP-PKA-K⁺ signaling to strengthen connectivity and thus enhance neuronal firing. Note that emerging data suggest that HCN channels on PFC spines may open neighboring K⁺ channels (El Hassar, Arnsten, Datta and Kaczmarek, unpublished), and thus behave as an ion channel complex. (B) ImmunoEM shows that α2A-AR are co-localized with HCN channels on layer III dlPFC spines. Adapted from (Wang et al., 2007) with permission; image originally created by C. Paspalas. (C) Iontophoresis of guanfacine onto a dlPFC Delay cell enhances task-related firing (highlit in green). Adapted from (Wang et al., 2007) with permission; image originally created by M. Wang. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Guanfacine counteracts the effects of chronic stress in PFC. (A) A schematic illustration showing how stress increases, while guanfacine inhibits, the feedforward Ca²⁺-cAMP-PKA-K⁺ actions that weaken PFC network connectivity, neuronal firing and function. α2A-AR are also expressed on activated microglia, where α2A-AR stimulation deactivates microglia and thus has anti-inflammatory actions. (B) Example of a layer II/III mPFC pyramidal cell distal dendrite from a control vs. chronic stressed rat, showing the reduced spine density in the stressed PFC. Scale bar indicates 25 μm. Adapted from (Hains et al., 2009) with permission. (C) Chronic stress (Str) exposure reduces PFC spine density in vehicle-treated rats, but not in those receiving daily guanfacine treatment. Con = control; Str = chronic stress; Veh = vehicle; Gfc = guanfacine. Adapted from (Hains et al., 2015) with permission.

Fig. 7

Guanfacine improves working memory across species. (A) Mouse models are particularly helpful for using genetic alterations to assess molecular mechanisms. Images show the α2A-AR, and a schematic diagram of the mouse brain with the location of the prelimbic (PL) subregion of the mPFC indicated. The lower graph shows that systemic administration of guanfacine improves working memory performance in wild-type but not α2A-AR mutant mice; adapted from (Franowicz et al., 2002) with permission. (B) Infusion of guanfacine (GFC) into the aged rat PL mPFC improves working memory performance. Top- the locations of the infusion cannula tips in mPFC. Bottom- The enhancement with guanfacine is reversed by co-infusion of the cAMP-PKA agonist, Sp-cAMPS (Sp), using a low dose with no effects on its own. Adapted with permission from (Ramos et al., 2006). (C) Guanfacine improves working memory under distracting conditions in aged monkeys. Top- the location of the dlPFC subregion subserving visuospatial working memory in the macaque brain is highlit in green. Bottom- Adding distractors (DIST) during the delay period impairs performance of a working memory task if aged monkeys are pretreated with saline (SAL) but performance is protected with guanfacine (GFC) pretreatment. CON = control. Adapted with permission from (Arnsten & Contant, 1992). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 8

Mental disorders where treatment with guanfacine is either approved for treatment, is used off-label, or is under experimental investigation.