Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

Neuropsychopharmacology. 2016 May;41(6):1579-87. doi: 10.1038/npp.2015.316. Epub 2015 Oct 16.

Abstract

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 β2 subunit-containing (β2*) and α7 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 β2 or α7 nAChR subunit in the amygdala all induced robust anxiolytic- and antidepressant-like effects in several mouse behavioral models. Further, whereas α7 nAChR subunit knockdown was somewhat more effective at decreasing anxiety-like behavior, only β2 subunit knockdown decreased resilience to social defeat stress and c-fos immunoreactivity in the BLA. In contrast, α7, but not β2, subunit knockdown effectively reversed the effect of increased ACh signaling in a mouse model of depression. These results suggest that signaling through β2* nAChRs is essential for baseline excitability of the BLA, and a decrease in signaling through β2 nAChRs alters anxiety- and depression-like behaviors even in unstressed animals. In contrast, stimulation of α7 nAChRs by acetylcholine may mediate the increased depression-like behaviors observed during the hypercholinergic state observed in depressed individuals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amygdala / physiology*
  • Animals
  • Male
  • Mecamylamine / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nicotinic Antagonists / pharmacology
  • Physostigmine / pharmacology
  • Receptors, Nicotinic / physiology*
  • Signal Transduction / physiology
  • Stress, Psychological / physiopathology*
  • alpha7 Nicotinic Acetylcholine Receptor / antagonists & inhibitors
  • alpha7 Nicotinic Acetylcholine Receptor / physiology

Substances

  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • nicotinic receptor beta2
  • Mecamylamine
  • Physostigmine