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Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

Perkins, Adam and Patrick, Fiona and Wise, Toby 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 Rathjen, Deborah and Macare, Christine and Williams, Steven C. R. and Young, Allan H. (2021) Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder. Translational Psychiatry, 11 . Art. No. 13. ISSN 2158-3188. https://resolver.caltech.edu/CaltechAUTHORS:20210112-151232254

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Abstract

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41398-020-01141-5DOIArticle
ORCID:
AuthorORCID
Perkins, Adam0000-0002-9162-0189
Patrick, Fiona0000-0002-6241-6517
Wise, Toby0000-0002-9021-3282
Doolin, Elizabeth0000-0002-8972-7315
Williams, Steven C. R.0000-0003-4299-1941
Young, Allan H.0000-0003-2291-6952
Additional Information:© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. The study was funded by Bionomics Ltd to Allan H. Young and Adam M. Perkins. Allan H. Young, Steve C. R. Williams and Adam M. Perkins 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. Toby Wise is funded by a Wellcome Trust Sir Henry Wellcome fellowship. Conflict of interest. A.H.Y. and S.C.R.W. are members of the Bionomics Scientific Advisory Board. S.M.O’C. and E.D. 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; trial/2014-004937-15/GB; BNC210.006.
Funders:
Funding AgencyGrant Number
Bionomics LtdUNSPECIFIED
National Institute for Health Research Biomedical Research CentreUNSPECIFIED
Maudsley National Health Service Foundation TrustUNSPECIFIED
King’s College LondonUNSPECIFIED
Wellcome TrustUNSPECIFIED
Record Number:CaltechAUTHORS:20210112-151232254
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210112-151232254
Official Citation:Perkins, A., Patrick, F., Wise, T. et al. Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder. Transl Psychiatry 11, 13 (2021). https://doi.org/10.1038/s41398-020-01141-5
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107448
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:13 Jan 2021 16:00
Last Modified:13 Jan 2021 16:00

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