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

Abstract Background Generalised anxiety disorder is associated with hyperactivity in amygdala-prefrontal networks, and normalisation 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 has not been investigated. Methods We administered a novel α7 nicotinic acetylcholine receptor negative allosteric modulator, BNC210, to 24 individuals (3 male) with generalised anxiety disorder and assessed its effects on neural responses to fearful face stimuli.materials-methods Results BNC210 reduced amygdala reactivity to fearful faces relative to placebo, 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.results Conclusions These results demonstrate for the first time that the function of disorder relevant neural circuits in generalised anxiety disorder can be beneficially altered through modulation of cholinergic neurotransmission and suggests potential for this system as a novel target for anxiolytic pharmacotherapy.results