Journal
NEUROPSYCHOPHARMACOLOGY
Volume 41, Issue 6, Pages 1579-1587Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2015.316
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Funding
- NIH from the National Institute on Drug Abuse (NIDA) [DA033945, MH077681, MH105824]
- Food and Drug Administration (FDA)
- Office of Research on Women's Health (ORWH)
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Electrophysiological and neurochemical studies implicate cholinergic signaling in the basolateral amygdala (BLA) in behaviors related to stress. Both animal studies and human clinical trials suggest that drugs that alter nicotinic acetylcholine receptor (nAChR) activity can affect behaviors related to mood and anxiety. Clinical studies also suggest that abnormalities in cholinergic signaling are associated with major depressive disorder, whereas pre-clinical studies have implicated both beta 2 subunit-containing (beta 2*) and alpha 7 nAChRs in the effects of nicotine in models of anxiety- and depression-like behaviors. We therefore investigated whether nAChR signaling in the amygdala contributes to stress-mediated behaviors in mice. Local infusion of the non-competitive non-selective nAChR antagonist mecamylamine or viral-mediated downregulation of the beta 2 or alpha 7 nAChR subunit in the amygdala all induced robust anxiolytic- and antidepressant-like effects in several mouse behavioral models. Further, whereas alpha 7 nAChR subunit knockdown was somewhat more effective at decreasing anxiety-like behavior, only beta 2 subunit knockdown decreased resilience to social defeat stress and c-fos immunoreactivity in the BLA. In contrast, alpha 7, but not beta 2, subunit knockdown effectively reversed the effect of increased ACh signaling in a mouse model of depression. These results suggest that signaling through beta 2* nAChRs is essential for baseline excitability of the BLA, and a decrease in signaling through beta 2 nAChRs alters anxiety- and depression-like behaviors even in unstressed animals. In contrast, stimulation of alpha 7 nAChRs by acetylcholine may mediate the increased depression-like behaviors observed during the hypercholinergic state observed in depressed individuals.
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