Background: There is compelling evidence that genetic factors play a major role in the development of alcohol dependence. Platelet adenylyl cyclase (AC) activity has been proposed as a biochemical marker for differentiating alcohol-dependent and nondependent subjects, but the sensitivity and specificity of this marker have not been ascertained. The objective of this study was to determine the sensitivity and specificity of platelet AC activity in identifying alcohol-dependent subjects and to ascertain the effect of medical/ psychiatric variables, drinking and smoking history, and age and body weight on AC activity.Methods: The cross-sectional study was conducted from 1995 to 1998. Participants were 210 Australian White men who were community volunteers and alcohol treatment inpatients in Sydney, Australia. There were 41 nondrinkers, 140 drinkers, and 29 men who were entering alcohol treatment. The main outcome measure was platelet AC activity. Classification variables were plasma ethanol, ␥-glutamyltransferase, aspartate aminotransferase, serum carbohydrate-deficient transferrin (CDT), and urinary 5-hydroxytryptophol/5-hydroxyindoleacetic acid (5-HTOL/5-HIAA) levels, and World Health Organization/International Society for Biomedical Research on Alcoholism Interview Schedule variables, which included alcohol use and dependence criteria.Results: Among subjects who reported abstinence for at least 4 days, both cesium fluoride (CsF)-and forskolin-stimulated platelet AC activities were significantly lower in those with a lifetime history of alcohol dependence compared with those with no such history (p Ͻ 0.005 and p Ͻ 0.05, respectively). The sensitivity and specificity of CsF-stimulated AC activity to discriminate individuals with a lifetime history of alcohol dependence were 75% and 79%, respectively. Similar values for sensitivity and specificity for CsFstimulated AC activity were calculated when discriminating current alcohol dependence in the subjects in our sample. Irrespective of the history of alcohol dependence, persons who had consumed alcohol recently (within the last 3-4 days) showed significantly higher mean basal, CsF-stimulated, and forskolin-stimulated AC activity (p Ͻ 0.001), as did those who had elevated 5-HTOL/5-HIAA ratios or CDT levels, indicative of recent (heavy) drinking. The "normalization" of platelet AC activity to baseline levels after an individual stops drinking may be related to the generation of new platelets during the abstinence period. Conduct disorder and antisocial personality disorder were not associated with low AC activity, but low forskolinstimulated AC activity was associated with major depression.Conclusions: We found that CsF-and forskolin-stimulated platelet AC activity discriminates between subjects with and without alcohol dependence in a population of subjects who had not consumed significant quantities of ethanol recently. Recent alcohol consumption is a confounding variable that can alter the measured levels of AC activity. Forskolin-stimulated platelet AC activity al...