Interaction between noradrenergic and cholinergic signaling in amygdala regulates anxiety- and depression-related behaviors in mice

Abstract

Medications that target the noradrenergic system are important therapeutics for depression and anxiety disorders. More recently, clinical studies have shown that the α2-noradrenergic receptor (α2AR) agonist guanfacine can decrease stress-induced smoking relapse during acute abstinence, suggesting that targeting the noradrenergic system may aid in smoking cessation through effects on stress pathways in the brain. Acetylcholine (ACh), like the nicotine in tobacco, acts at nicotinic acetylcholine receptors (nAChRs) to regulate behaviors related to anxiety and depression. We therefore investigated interactions between guanfacine and ACh signaling in tests of anxiolytic and antidepressant efficacy in female and male C57BL/6J mice, focusing on the amygdala as a potential site of noradrenergic/cholinergic interaction. The antidepressant-like effects of guanfacine were blocked by shRNA-mediated knockdown of α2AR in amygdala. Knockdown of the high-affinity β2 nAChR subunit in amygdala also prevented antidepressant-like effects of guanfacine, suggesting that these behavioral effects require ACh signaling through β2-containing nAChRs in this brain area. Ablation of NE terminals prevented the anxiolytic- and antidepressant-like effects of the nicotinic partial agonist cytisine, whereas administration of the cholinesterase antagonist physostigmine induced a depression-like phenotype that was not altered by knocking down α2AR in the amygdala. These studies suggest that ACh and NE have opposing actions on behaviors related to anxiety and depression and that cholinergic signaling through β2-containing nAChRs and noradrenergic signaling through α2a receptors in neurons of the amygdala are critical for regulation of these behaviors.

Determinants of anxiety and depression among pheochromocytoma patients

“…The dysfunction of the noradrenergic system has been confirmed as the principal cause of depression and anxiety disorders. [ 18 ] The amygdala is a potential site of noradrenergic/cholinergic interaction. Noradrenergic signaling through α2A receptors in neurons in the amygdala is critical for the regulation of depression and anxiety disorders.…”

Variability in nicotine conditioned place preference and stress‐induced reinstatement in mice: Effects of sex, initial chamber preference, and guanfacine

“…However, it is unclear why guanfacine would have this effect. Guanfacine also has anxiolytic‐ and antidepressant‐like effects, and enhances working memory . Perhaps guanfacine enhanced spatial working memory for the initially preferred context, thereby increasing time spent in that chamber …”

Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics

“…Specifically, α7 subunit knockdown in the amygdala produced antidepressant-like effects in the TST 159 , while β2* subunit knockdown produced antidepressant-like effects in the FST, TST, and the social defeat paradigm 159 . β2* subunit knockdown in the amygdala was also found to be critical for the antidepressant-like effects of the alpha2-noradrenergic receptor agonist guanfacine, while the antidepressant-like effects of the nicotinic partial agonist cytisine required noradrenergic signaling in the amygdala, highlighting an interaction between ACh and noradrenergic signaling in the regulation of depression-like behaviors in the mouse 164 . Furthermore, ACh signaling through α7 nAChRs in the hippocampus was reported to regulate depression-like behaviors when ACh levels are increased, which can occur under stressful conditions 76 .…”