Regional Brain Metabolic Response to Lorazepam in Subjects at Risk for Alcoholism

The mechanisms underlying the blunted response to alcohol administration observed in subjects at risk for alcoholism are poorly understood and may involve GABA-benrodiazepine receptors. The purpose of this study was to investigate if subjects at risk for alcoholism had abnormalities in brain GABA-benzodiazepine receptor function. This study measured the effects of 30 pg/kg (iv) of lorarepam, on regional brain glucose metabolism using positron emission tomography and 2-deoxy-2['8~f~uoro-o-g~ucose in subjects with a positive family history for alcoholism (FP) (n = 12) and compared their response with that of subjects with a negative family history for alcoholism (FN) (n = 21). At baseline, FP subjects showed lower cerebellar metabolism than FN. Lorazepam decreased wholebrain glucose metabolism, and FP subjects showed a similar response to FN in cortical and subcortical regions, but FP showed a blunted response in cerebellum. Lorazepam-induced changes in cerebellar metabolism correlated with its motor effects. The decreased cerebellar baseline metabolism in FP as well as the blunted cerebellar response to lorarepam challenge may reflect disrupted activity of benrodiazepine-GABA receptors in cerebellum. These changes could account for the decreased sensitivity to the motor effects of alcohol and benrodiazepines in FP subjects. HE IMPORTANCE of genetics in alcoholism has been T demonstrated in epidemiological studies showing a higher level of concordance for alcoholism in identical twins than in fraternal twins and by studies documenting a 4-fold increased risk for alcoholism in children of alcoholics than in the general population.'-' The influence of genetics in the differential sensitivity to ethanol has also been demonstrated in studies documenting that subjects at risk for alcoholism, that is children of alcoholics who themselves are not alcoholics, show a blunted response to alcohol when compared with subjects with a negative family history for alcoholism (FN).2,6 A blunted response to alcohol in family-positive subjects (FP) has been documented for the