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Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalised Anxiety Disorder

Wise, Toby and Patrick, Fiona and Meyer, Nicholas and Mazibuko, Ndaba and Oates, Alice E. and van der Bijl, Anne H. M. and Danjou, Philippe and O’Connor, Susan M. and Doolin, Elizabeth and Wooldridge, Caroline and Rathjan, Deborah and Macare, Christine and Williams, Steven C. R. and Perkins, Adam and Young, Allan H. (2020) Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalised Anxiety Disorder. Biological Psychiatry, 87 (10). pp. 908-915. ISSN 0006-3223. PMCID PMC7198974. https://resolver.caltech.edu/CaltechAUTHORS:20200108-131130552

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.biopsych.2019.12.013DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198974/PubMed CentralArticle
ORCID:
AuthorORCID
Wise, Toby0000-0002-9021-3282
Patrick, Fiona0000-0002-6241-6517
Doolin, Elizabeth0000-0002-8972-7315
Williams, Steven C. R.0000-0003-4299-1941
Young, Allan H.0000-0003-2291-6952
Additional Information:© 2020 Society of Biological Psychiatry. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 21 May 2019, Revised 25 November 2019, Accepted 11 December 2019, Available online 8 January 2020. The study was funded by Bionomics Ltd (to AHY and AMP). AHY, SCRW, and AMP are supported by the National Institute for Health Research Biomedical Research Centre at the South London and Maudsley National Health Service Foundation Trust and King’s College London. This report represents independent research funded by the National Institute for Health Research Biomedical Research Centre and South London and Maudsley National Health Service Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the National Health Service, National Institute for Health Research, or Department of Health. TW is funded by a Wellcome Trust Sir Henry Wellcome fellowship. AHY and SCRW are members of the Bionomics Scientific Advisory Board. SMO and ED are employed by Bionomics Ltd. All other authors report no biomedical financial interests or potential conflicts of interest. EU Clinical Trials Register: A Randomized, Double-Blinded, Placebo and Lorazepam-Controlled, Four-Way Crossover, Phase II Study to Evaluate the Effects of Single Oral Administration of BNC210 on Brain Activity Changes Captured by Functional Magnetic Resonance Imaging in Adults With Generalized Anxiety Disorder; https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-004937-15/GB; BNC210.006.
Funders:
Funding AgencyGrant Number
Bionomics Ltd.UNSPECIFIED
National Institute for Health ResearchUNSPECIFIED
Maudsley National Health Service Foundation TrustUNSPECIFIED
King’s College LondonUNSPECIFIED
Wellcome TrustUNSPECIFIED
Subject Keywords:Amygdala; Anterior cingulate cortex; Cholinergic modulation; Generalized anxiety disorder; fMRI; Pharmacotherapy
Issue or Number:10
PubMed Central ID:PMC7198974
Record Number:CaltechAUTHORS:20200108-131130552
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200108-131130552
Official Citation:Toby Wise, Fiona Patrick, Nicholas Meyer, Ndaba Mazibuko, Alice E. Oates, Anne H.M. van der Bijl, Philippe Danjou, Susan M. O’Connor, Elizabeth Doolin, Caroline Wooldridge, Deborah Rathjen, Christine Macare, Steven C.R. Williams, Adam Perkins, Allan H. Young, Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder, Biological Psychiatry, Volume 87, Issue 10, 2020, Pages 908-915, ISSN 0006-3223, https://doi.org/10.1016/j.biopsych.2019.12.013. (http://www.sciencedirect.com/science/article/pii/S0006322319319377)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:100559
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:08 Jan 2020 22:12
Last Modified:25 Nov 2020 00:18

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