TY - JOUR
T1 - Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder
AU - Perkins, Adam
AU - Patrick, Fiona
AU - Wise, Toby
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 - Young, Allan H
N1 - Funding Information:
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.
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098849413&partnerID=8YFLogxK
U2 - 10.1038/s41398-020-01141-5
DO - 10.1038/s41398-020-01141-5
M3 - Article
C2 - 33414442
SN - 2158-3188
VL - 11
SP - 13
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 13
ER -
