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

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.

Fig. 1. The ethoexperimental approach to measuring the intensity of threat-avoidance behaviour.

a The Mouse Defense Test Battery. b The Joystick Operated Runway Task. A force-sensing interface controls the speed of a green dot cursor pursued along a runway by a red dot cursor capable of inflicting electric shock. The task comprised 12 trials each of pursuit (c), pursuit plus threat of electric shock (d), goal conflict (e), goal conflict plus threat of electric shock (f). Illustration by Nick Boon.

Fig. 2. Flow chart showing the exclusion path and numbers.

Abbreviations: TSDI, Trait Self-Description Inventory; MINI, Mini International Neuropsychiatric Interview; GAD, generalised anxiety disorder; MADRS, Montgomery-Asberg Depression Rating Scale; MRI, magnetic resonance imaging.

Fig. 3. Drug effects on Spielberger State Anxiety.

State anxiety was significantly decreased by the low dose of BNC210 (n = 21, error bars = 1 SEM).

Fig. 4. Drug effects on Flight Intensity as measured by the Joystick Operated Runway Task (JORT).

Flight Intensity was significantly decreased by both low and high doses of BNC210 but not by lorazepam (n = 21, error bars = 1 SEM).

Fig. 5. Drug effects on Risk Assessment Intensity as measured by the Joystick Operated Runway Task (JORT).

Risk Assessment Intensity was not significantly altered by BNC210 or lorazepam (n = 21, error bars = 1 SEM).