GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study.
BACKGROUND
Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence.


OBJECTIVE
We used positron emission tomography (PET) with [11C]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 [11C]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 [11C]flumazenil between the plasma and brain compartments were derived from time activity curves.


RESULTS
A 50% reduction in electroencephalography (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 beta1 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.
Lingford-Hughes
A R
AR
Psychopharmacology Unit, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK. anne.lingford-hughes@bristol.ac.uk
Wilson
S J
SJ
Cunningham
V J
VJ
Feeney
A
A
Stevenson
B
B
Brooks
D J
DJ
Nutt
D J
DJ
D000328:Adult; D000437:Alcoholism / Q000378:metabolism*; D000704:Analysis of Variance; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D016022:Case-Control Studies; D003164:Competitive Bidding / Q000379:methods; D004569:Electroencephalography / Q000379:methods; D005442:Flumazenil / Q000493:pharmacokinetics*; D018757:GABA Modulators / Q000097:blood / Q000493:pharmacokinetics*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008297:Male; D008874:Midazolam / Q000097:blood / Q000494:pharmacology; D008875:Middle Aged; D010147:Pain Measurement / Q000379:methods; D049268:Positron-Emission Tomography; D011963:Receptors, GABA-A / Q000502:physiology*; D012438:Saccades / Q000187:drug effects; D012720:Severity of Illness Index; D012890:Sleep / Q000187:drug effects; D013732:Test Anxiety Scale / Q000706:statistics & numerical data; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D018757:GABA Modulators; D011963:Receptors, GABA-A; D014316:Tritium; D005442:Flumazenil; D008874:Midazolam