Altered benzodiazepine receptor sensitivity in alcoholism: A study with fMRI and acute lorazepam challenge

Abstract 

Previous studies suggested altered sensitivity of the GABA/benzodiazepine receptor system in alcoholic patients. Expanding on these findings, the present functional magnetic resonance imaging (fMRI) study aimed to assess whether a differential modulation of cognitive brain activation by an acute GABAergic drug challenge could be detected in patients with alcoholism. Eight detoxified male patients meeting DSM-IV criteria for alcohol dependence and nine healthy male control subjects were studied with fMRI while performing a 2-back working memory task. The fMRI scans were performed 1 h after intravenous administration of saline and again 1 h after 0.03 mg/kg lorazepam I.V. After saline, a task × group interaction effect with higher task activation in alcoholic patients in the left cerebellum and the right prefrontal cortex emerged. Additionally, a differential task × drug × group interaction was identified in the right cerebellum with more pronounced reduction in cognitive activation after lorazepam in the patient group. A significant correlation between lorazepam sensitivity and duration of alcohol dependence was detected. The present findings are in line with previous studies suggesting disrupted prefrontal–cerebellar activation with potential compensatory hyperactivation of the compromised brain networks in alcoholism. Moreover, the results suggest enhanced responsivity to an acute GABAergic challenge in the right cerebellum with disease-related disruption of cerebellar functional integrity.

Keywords: Alcohol, gamma-aminobutyric acid, Benzodiazepines, Cognition, Working memory, Cerebellum