Chronic stimulation of alpha-2A-adrenoceptors with guanfacine protects rodent prefrontal cortex dendritic spines and cognition from the effects of chronic stress

Abstract

The prefrontal cortex (PFC) provides top-down regulation of behavior, cognition, and emotion, including spatial working memory. However, these PFC abilities are greatly impaired by exposure to acute or chronic stress. Chronic stress exposure in rats induces atrophy of PFC dendrites and spines that correlates with working memory impairment. As similar PFC grey matter loss appears to occur in mental illness, the mechanisms underlying these changes need to be better understood. Acute stress exposure impairs PFC cognition by activating feedforward cAMP-calcium- K+ channel signaling, which weakens synaptic inputs and reduces PFC neuronal firing. Spine loss with chronic stress has been shown to involve calcium-protein kinase C signaling, but it is not known if inhibiting cAMP signaling would similarly prevent the atrophy induced by repeated stress. The current study examined whether inhibiting cAMP signaling through alpha-2A-adrenoceptor stimulation with chronic guanfacine treatment would protect PFC spines and working memory performance during chronic stress exposure. Guanfacine was selected due to 1) its established effects on cAMP signaling at post-synaptic alpha-2A receptors on spines in PFC, and 2) its increasing clinical use for the treatment of pediatric stress disorders. Daily guanfacine treatment compared to vehicle control was found to prevent dendritic spine loss in layer II/III pyramidal neurons of prelimbic PFC in rats exposed to chronic restraint stress. Guanfacine also protected working memory performance; cognitive performance correlated with dendritic spine density. These findings suggest that chronic guanfacine use may have clinical utility by protecting PFC gray matter from the detrimental effects of stress.

Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia

“…150,151 These morphological changes are correlated with deficits in working memory in the delayed alternation task 152 and cognitive flexibility on perceptual set-shifting tasks 153 and can be prevented blocking PKA 154 or PKC 152 signaling, consistent with an underlying role of dysregulated DNC signaling. Dendritic atrophy and loss of spines are brain region-specific; in contrast to the PFC, chronic stress actually increases dendrite morphogenesis in the amygdala.…”

“…134 Electrophysiology studies in nonhuman primates show that α 2A-AR inhibition of cAMP-HCN signaling enhances dlPFC firing, 134 and either intra-PFC or systemic treatment with guanfacine strengthens PFC function. 205 Particularly pertinent to schizophrenia, daily guanfacine treatment is also protective of PFC dendritic spines and cognitive functions in a chronic restrained stress paradigm, 154 or from hypoxia, 206 in rat medial PFC, encouraging this approach. As α 2A-AR-agonists such as guanfacine are also anti-inflammatory, deactivating microglia, 207 they may also be more generally protective of brain during the prodrome.…”

Animal models for posttraumatic stress disorder: An overview of what is used in research

“…Studies using this model demonstrated increased negative HPA feedback similar to that observed in PTSD [23] . Acute and chronic restraint both generate significantly increased behavioural anxiety and nociception [33] , but the effects of chronic restraint stress can be protected against by stimulating alpha-2A adrenoceptors with guanfacine [34] .…”

Effects of Chronic Stress on Cognition in Male SAMP8 Mice

“…Stress is associated with several diseases, including anxiety disorders and other psychiatric diseases [12], and it can also lead to a cognitive deficit. Several studies [13][14][15][16][17] have demonstrated the detrimental effects of chronic stress on cognitive function, and many studies have found that a higher vulnerability to chronic stress is related to brain aging [18][19][20]. However, the neurological mechanisms underlying this effect are not well known.…”