GABA-benzodiazepine receptor function in alcohol dependence:: a combined 11C-flumazenil PET and pharmacodynamic study

Rationale: Gamma-aminobutyric acid (GABA)benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. Objectives: We used positron emission tomography (PET) with [C-11]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Methods: Abstinent male alcohol dependent subjects underwent [C-11] flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [C-11]flumazenil between the plasma and brain compartments were derived from time activity curves. Results: A 50% reduction in electro- encephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG betal power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. Conclusions: In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.