Benzodiazepines counteract rostral anterior cingulate cortex activation induced by cholecystokinin-tetrapeptide in humans.

Background: Benzodiazepines modulate γ-aminobutyric acid type A (GABA(A)) receptors throughout the brain. However, it is not fully understood which brain regions within anxiety-related brain circuits are really responsible for their anxiolytic effects and how these regions interact.

Methods: We investigated whether the benzodiazepine alprazolam affects activity in distinct brain regions within anxiety-related circuits during an experimental anxiety paradigm by means of functional magnetic resonance imaging (fMRI). Panic symptoms were elicited by a bolus injection of the neuropeptide cholecystokinin-tetrapeptide (CCK-4) in 16 healthy male subjects in a double-blind, placebo-controlled design. Functional brain activation patterns were determined before and during the CCK-4-challenge without pretreatment and after treatment with either placebo or 1 mg alprazolam.

Results: The CCK-4 induced anxiety and elicited widely distributed activation patterns in anxiety-related brain circuits, especially in the rostral anterior cingulate cortex (rACC), which was attenuated after alprazolam treatment. In contrast to placebo, alprazolam abolished the activation of the rACC after challenge with CCK-4 (p<.005, corrected for multiple comparisons) and increased functional connectivity between the rACC and other anxiety-related brain regions such as amygdala and prefrontal cortex. Moreover, the reduction in the CCK-4 induced activation of the rACC correlated with the anxiolytic effect of alprazolam (r(p) = .52; p = .04).

Conclusions: These findings put forward the rACC as a target for benzodiazepines and suggest that the CCK-4/fMRI paradigm might represent a human translational model for the investigation of anxiolytic drugs.