TY - JOUR
T1 - Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder
AU - Wise, Toby
AU - Patrick, Fiona
AU - Meyer, Nicholas
AU - Mazibuko, Ndaba
AU - Oates, Alice E
AU - van der Bijl, Anne H M
AU - Danjou, Philippe
AU - O'Connor, Susan M
AU - Doolin, Elizabeth
AU - Wooldridge, Caroline
AU - Rathjen, Deborah
AU - Macare, Christine
AU - Williams, Steven C R
AU - Perkins, Adam
AU - Young, Allan H
N1 - Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
PY - 2020/5/15
Y1 - 2020/5/15
N2 - BACKGROUND: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefrontal networks, and normalization of this aberrant function is thought to be critical for successful treatment. Preclinical evidence implicates cholinergic neurotransmission in the function of these systems and suggests that cholinergic modulation may have anxiolytic effects. However, the effects of cholinergic modulators on the function of anxiety-related networks in humans have not been investigated.METHODS: We administered a novel α7 nicotinic acetylcholine receptor-negative allosteric modulator, BNC210, to 24 individuals (3 male subjects) with generalized anxiety disorder and assessed its effects on neural responses to fearful face stimuli.RESULTS: BNC210 reduced amygdala reactivity to fearful faces relative to placebo and similarly to lorazepam and also reduced connectivity between the amygdala and the anterior cingulate cortex, a network involved in regulating anxious responses to aversive stimuli.CONCLUSIONS: These results demonstrate for the first time that the function of disorder-relevant neural circuits in generalized anxiety disorder can be beneficially altered through modulation of cholinergic neurotransmission and suggest potential for this system as a novel target for anxiolytic pharmacotherapy.
AB - BACKGROUND: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefrontal networks, and normalization of this aberrant function is thought to be critical for successful treatment. Preclinical evidence implicates cholinergic neurotransmission in the function of these systems and suggests that cholinergic modulation may have anxiolytic effects. However, the effects of cholinergic modulators on the function of anxiety-related networks in humans have not been investigated.METHODS: We administered a novel α7 nicotinic acetylcholine receptor-negative allosteric modulator, BNC210, to 24 individuals (3 male subjects) with generalized anxiety disorder and assessed its effects on neural responses to fearful face stimuli.RESULTS: BNC210 reduced amygdala reactivity to fearful faces relative to placebo and similarly to lorazepam and also reduced connectivity between the amygdala and the anterior cingulate cortex, a network involved in regulating anxious responses to aversive stimuli.CONCLUSIONS: These results demonstrate for the first time that the function of disorder-relevant neural circuits in generalized anxiety disorder can be beneficially altered through modulation of cholinergic neurotransmission and suggest potential for this system as a novel target for anxiolytic pharmacotherapy.
KW - Amygdala
KW - Anterior cingulate cortex
KW - Cholinergic modulation
KW - Generalized anxiety disorder
KW - Pharmacotherapy
KW - fMRI
UR - http://www.scopus.com/inward/record.url?scp=85080033143&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2019.12.013
DO - 10.1016/j.biopsych.2019.12.013
M3 - Article
C2 - 32107005
SN - 0006-3223
VL - 87
SP - 908
EP - 915
JO - Biological psychiatry
JF - Biological psychiatry
IS - 10
M1 - BPS-D-19-00755R1
ER -