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

Abstract

Background: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefrontal networks, and normalization 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 have not been investigated.

Methods: We administered a novel α7 nicotinic acetylcholine receptor-negative allosteric modulator, BNC210, to 24 individuals (3 male subjects) with generalized anxiety disorder and assessed its effects on neural responses to fearful face stimuli.

Results: BNC210 reduced amygdala reactivity to fearful faces relative to placebo and 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.

Conclusions: These results demonstrate for the first time that the function of disorder-relevant neural circuits in generalized anxiety disorder can be beneficially altered through modulation of cholinergic neurotransmission and suggest potential for this system as a novel target for anxiolytic pharmacotherapy.

Keywords: Amygdala; Anterior cingulate cortex; Cholinergic modulation; Generalized anxiety disorder; Pharmacotherapy; fMRI.

Figure 1

Illustration of the four dosing procedures. MRI, magnetic resonance imaging.

Figure 2

(A) Mean (±SE) amygdala response to fearful faces for each drug condition. (B) Effect of BNC210 low dose on amygdala activity, thresholded at p < .05 uncorrected for illustration. *p < .05, **p < .01.

Figure 3

(A) Mean functional connectivity strength with amygdala seeds while viewing fearful faces in the anterior cingulate cortex cluster. (B) Anterior cingulate cortex cluster showing significant reductions in functional connectivity strength with the amygdala under BNC210 (low dose) in the psychophysiological interaction analysis.