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...

Platelet Adenylyl Cyclase Activity as a State or Trait Marker in Alcohol Dependence: Results of the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence

“…These diagnoses, as well as answers to certain specific questions in the interview, as listed in "Methods," were used to construct multiple linear regression models. The variables chosen for testing in the models were based on our previous work (Ikeda et al, 1998;Menninger et al, 1998Menninger et al, , 2000Menninger and Tabakoff, 1997;Tabakoff et al, 1988) and that of others (e.g., Lex et al, 1993;Waltman et al, 1993), which indicated particular factors that were associated with influences on platelet adenylyl cyclase.…”

“…The WHO/ISBRA Interview Schedule is described by Menninger et al (2000) and by Glanz and Tabakoff (2002). Alcohol-dependent and alcohol-abusing subjects met the appropriate DSM-IV criteria (American Psychiatric Association, 1994), and for the analysis in the present study, subjects were categorized as alcohol dependent or alcohol abusers, regardless of their reported level of alcohol drinking.…”

“…Without the use of the HEL cell membrane standardization factor, interassay coefficients of variability for AC activities in our laboratory have been reported as follows: basal, 23.4%; CsF-stimulated, 9.2%; and forskolin-stimulated, 13.5% . With the use of the HEL cell membrane standardization factor, interassay coefficients of variability were found to be 15.4%, 10.8%, and 11.9% for basal, CsF-stimulated, and forskolin-stimulated AC activity, respectively (Menninger et al, 2000).…”

“…A number of studies have shown that AC activity in platelets or lymphocytes of alcohol-dependent individuals is less responsive to various stimulators (e.g., fluoride ion, guanine nucleotide analogs, forskolin) than activity in cells of control subjects (Diamond et al, 1987;Lex et al, 1993;Menninger et al, 1998Menninger et al, , 2000Nagy et al, 1988;Saito et al, 1994;Tabakoff et al, 1988;Waltman et al, 1993). Although it is often difficult to determine if such a difference is a result of alcohol drinking or reflects an inherent difference between alcohol-dependent subjects and controls, the results from many of these studies were consistent with the hypothesis that platelet or lymphocyte AC activity could represent a trait marker for alcohol dependence.…”

“…Although it is often difficult to determine if such a difference is a result of alcohol drinking or reflects an inherent difference between alcohol-dependent subjects and controls, the results from many of these studies were consistent with the hypothesis that platelet or lymphocyte AC activity could represent a trait marker for alcohol dependence. On the other hand, recent work has demonstrated clearly that platelet AC activity decreases over a period of abstinence after heavy drinking (Menninger et al, , 2000, and most of the studies of AC activity in alcohol-dependent individuals found lower activity in those subjects who had been abstinent from alcohol for some period of time before testing (Lex et al, 1993;Menninger et al, 1998;Saito et al, 1994;Tabakoff et al, 1988). In view of these results, platelet AC activity may be considered to be a state marker in that it is influenced by alcohol drinking or abstinence.…”