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.

Antidepressant-Like Properties of Intrastriatal Botulinum Neurotoxin-A Injection in a Unilateral 6-OHDA Rat Model of Parkinson’s Disease

“…Since the neurobiology and etiology of treatment options of depression in PD are not fully understood, we tested here the effect of the injection of 1 ng BoNT-A into the DA-depleted CPu of hemi-PD rats on depression-like and anxiety-like behaviors. It is known that the cholinergic system, including the striatum, plays a central role not only in cognition but also in depression [ 121 , 122 , 123 , 124 , 125 , 126 , 127 ] and anxiety [ 128 , 129 , 130 , 131 , 132 , 133 , 134 ].…”

Negative and positive allosteric modulators of the α7 nicotinic acetylcholine receptor regulates the ability of adolescent binge alcohol exposure to enhance adult alcohol consumption

“…BNC210 has been shown to reduce the expression of Seasonal Affect Disorder (SAD) and the altered neurocircuit activity profile associated with this disorder (Wise et al, 2020 ). BNC210 has also been shown to be efficacious at reducing the symptoms of General Anxiety Disorder (GAxD) and may have anxiolytic properties (Perkins et al, 2021 ). BNC210 has been given FastTrack Designation by the US FDA for the treatment of SAD and GAxD (Perkins et al, 2021 ).…”

“…BNC210 has also been shown to be efficacious at reducing the symptoms of General Anxiety Disorder (GAxD) and may have anxiolytic properties (Perkins et al, 2021 ). BNC210 has been given FastTrack Designation by the US FDA for the treatment of SAD and GAxD (Perkins et al, 2021 ). BNC210 is currently being assessed for treatment of PTSD.…”

Are Fear and Anxiety Truly Distinct?

“…( 53 ) For Human Lorazepam has dose-dependent effect on risk assessment but no effect on fear Perkins et al. ( 54 ) For Human BNC210 reduces flight intensity but not risk-assessment intensity SAD, social anxiety disorder. …”

“…Subsequently, the same group found an effect of lorazepam on anxiety but at a lower dose (0.5 mg), while the previously effective dose (1 mg) did not differ from placebo ( 52 ). Moreover, there was conflicting evidence for the influence of personality traits on fear/anxiety behaviors, as measured by the JORT ( 53 , 54 ), making it, overall, difficult to draw any conclusions with respect to the fear-anxiety distinction.…”