Platelet Adenylyl Cyclase Activity as a Trait Marker of Alcohol Dependence

Abstract

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...

Postmortem Brain Tissue of Depressed Suicides Reveals Increased Gsα Localization in Lipid Raft Domains Where It Is Less Likely to Activate Adenylyl Cyclase

“…for depression (Mooney et al, 1988(Mooney et al, , 1998Garcia-Sevilla et al, 1990;Pandey et al, 1990a,b;Menninger and Tabakoff, 1997;Menninger et al, 2000;Hoffman et al, 2002;Hines and Tabakoff, 2005). The most recent of these studies demonstrated markedly lower levels of basal, forskolin-, cesium fluoride-, and Gpp(NH)p-stimulated platelet adenylyl cyclase activity in subjects with a history of major depression compared with control subjects (Hines and Tabakoff, 2005).…”

Gene Expression in Brain: A Window on Ethanol Dependence, Neuroadaptation, and Preference

“…There were differences in several ion channel subunits, including sodium, potassium, and chloride channels, that could affect neuronal excitability. Adenylyl cyclase 2 (Adcy2) was 1.3-fold lower in iP; differences in adenylyl cyclases have been implicated in alcoholism (Menninger et al, 2000). Protein kinases and phosphatases are important in signal transduction and second messenger systems.…”

Laboratory Tests for Acute Alcohol Consumption: Results of the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence

“…Blood was drawn by venipuncture in Vacutainer tubes that contained ethylenediaminetetraacetic acid for preparation of plasma (Menninger et al, 2000). Plasma samples were stored at Ϫ70°C until forwarded in dry ice to the Helsinki coordination center (Finland) and further to the Helsinki assay center for determination of ethanol and methanol.…”