Reduced γ-aminobutyric AcidA-benzodiazepine binding sites in insular cortex of individuals with panic disorder

Context: Benzodiazepine drugs are highly effective anxiolytic medications, but the role of the benzodiazepine gamma-aminobutyric acid(A)-chloride ion channel macromolecular complex in the pathophysiologic mechanism of anxiety is not well understood. Previous human imaging studies have indicated involvement of specific regions of the brain in anxiety disorders, especially the frontal-prefrontal, temporal, and cingulate cortical and the limbic areas. Objective: To identify potential abnormalities of brain benzodiazepine receptor binding number and distribution in anxiety disorders. Setting and Participants: At the University of Michigan positron emission tomography facility, 11 individuals with DSM-IV-defined anxiety syndrome panic disorder were compared with 21 unaffected healthy control subjects. Design and Main Outcome Measure: In a between-group comparison, we used positron emission tomography and the benzodiazepine receptor ligand flumazenil labeled with carbon 11 to assess the regional brain pattern of receptor binding. Results: We observed decreased binding specifically in the insular cortex bilaterally. No binding abnormality was observed in any other brain region, and there was no evidence of abnormal cerebral blood flow anywhere in the brain. Individuals with panic disorder and comorbid depression, indicative of a more severe disorder, had the lowest binding. No significant correlations were observed for binding with age, sex, or duration of disorder. Conclusions: A previous smaller study with the same ligand reported a probable binding abnormality in the right insula. Because gamma-aminobutyric acid is a major inhibitory neurotransmitter in the brain and because benzodiazepines facilitate this effect of gamma-aminobutyric acid, decreased benzodiazepine binding is consistent with localized brain activation (ie, loss of inhibition). Because the insula is strongly involved in visceral-somatic afferent and efferent function, activation of the insula is consistent with the occurrence of the physical symptoms prominently associated with panic disorder.