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.
Psychiatry Neuroimaging Branch, University Medical Center Hamburg-Eppendorf, Department of Psychiatry and Psychotherapy, Psychiatry Neuroimiaging Branch, Hamburg, Germany. g.leicht@uke.de
Gregor
G
Leicht
Christoph
C
Mulert
Daniela
D
Eser
Philipp G
PG
Sämann
Matthias
M
Ertl
Anna
A
Laenger
Susanne
S
Karch
Oliver
O
Pogarell
Thomas
T
Meindl
Michael
M
Czisch
Rainer
R
Rupprecht
D000328:Adult; D000525:Alprazolam / Q000494:pharmacology* / Q000627:therapeutic use; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D001931:Brain Mapping; D004311:Double-Blind Method; D018757:GABA Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D013758:Tetragastrin
D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D013758:Tetragastrin; D000525:Alprazolam