Platelet adenylyl cyclase activity as a trait marker of alcohol dependence. WHO/ISBRA Collaborative Study Investigators. International Society for Biomedical Research on Alcoholism.

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, gamma-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 < 0.005 and p < 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 CsF-stimulated 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 < 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 forskolin-stimulated 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 also may be influenced by a history of major depression.

An initial study of the relationship between platelet adenylyl cyclase activity and alcohol use disorder criteria.

Low platelet adenylyl cyclase (AC) activity has been previously proposed to be a trait marker reflecting a genetic predisposition to alcohol dependence. To determine whether low platelet AC activity in alcohol-dependent subjects may be related to specific diagnostic criteria of DSM-IV and ICD-10 alcohol use disorders, we analyzed responses obtained in structured clinical interviews of 36 subjects who were determined to be alcohol-dependent Platelet AC activity when stimulated by guanylyl-imidodiphosphate [Gpp(NH)p] or forskolin was significantly lower in alcohol-dependent subjects as a group, compared with controls. When we analyzed the responses of the alcohol-dependent subjects to questions used to establish the diagnosis of alcohol abuse/dependence and dichotomized the subjects by positive or negative responses, we found that Gpp(NH)p- and forskolin-stimulated platelet AC activities were significantly lower among those alcohol-dependent subjects who had positive responses to questions related to drinking despite negative effects on mood ("Did you ever continue to drink even though you knew it was making you feel depressed, uninterested in things, or suspicious or distrustful of other people?"), drinking despite negative effects on health ("Did you ever continue to drink even though you knew it was causing you a health problem or making a health problem worse?"), or violence when drinking ("Did you get into physical fights while drinking or right after drinking?"). The alcohol-dependent subjects who had negative responses to these questions exhibited Gpp(NH)p- and forskolin-stimulated platelet AC activity that did not differ significantly from values in control subjects. The DSM-IV diagnosis of antisocial personality disorder did not distinguish alcohol-dependent subjects with regard to platelet AC activity. Gpp(NH)p and forskolin-stimulated AC activity may distinguish certain subtypes of alcoholics (i.e., those who develop negative mood in response to drinking, those who continue drinking despite health effects, and those who become violent while drinking).

Effects of abstinence and family history for alcoholism on platelet adenylyl cyclase activity.

Platelet adenylyl cyclase (AC) activity was measured in 32 alcohol-dependent subjects and 27 control subjects who were categorized as either family history-positive (FHP) or family history-negative (FHN) for alcoholism. The interview and blood sample collections were performed shortly after cessation of heavy drinking in the alcoholic group, and repeat blood samples were obtained at the end of the first and second weeks of monitored abstinence. Control subjects received the same interview and provided blood samples at the time of the interview. When subjects were not segregated for FHP or FHN status, there were no statistically significant differences in basal, cesium fluoride (CsF)-, or forskolin-stimulated mean AC activities between the controls and the alcoholics, at study entry or with 1 or 2 weeks of abstinence. On the other hand, over the 2-week course of sobriety from heavy drinking, the CsF-stimulated AC activity of FHP alcohol-dependent subjects decreased significantly (p = 0.03). FHP alcohol-dependent subjects after 2 weeks of sobriety had significantly lower mean CsF-stimulated AC activity than FHN controls (p = 0.04), whereas the FHN alcoholic subjects' CsF-stimulated AC activity did not differ significantly from FHN controls at this point in time. When all subjects were pooled and then categorized as either FHP or FHN, there was a significant difference in mean CsF-stimulated AC activity (p = 0.02) between the FHP and FHN subject groups. Genetic factors and abstinence appear to have roles in determining low platelet AC activity in alcoholic and nonalcoholic subjects. CsF-stimulated platelet AC activity, in particular, appears to act as a trait marker for a genetic vulnerability to developing alcoholism, but recent heavy drinking in male alcoholics is a factor that can mask differences between FHP and FHN subjects.

Forskolin-stimulated platelet adenylyl cyclase activity is lower in persons with major depression.

We investigated platelet adenylyl cyclase activity in 17 subjects with a history of major depression ("depressed subjects") and 20 controls. Forskolin was used to directly activate adenylyl cyclase, while guanine nucleotides (Gpp(NH)p) and fluoride ions were used to measure adenylyl cyclase activity modulated through the G proteins. Forskolin-stimulated adenylyl cyclase was significantly lower in the depressed subjects (p < 0.0005). There was a statistically significant difference in basal adenylyl cyclase activity between male depressed subjects and male controls. The basal adenylyl cyclase activity was also lower in female depressed subjects, but this difference did not reach statistical significance (p < 0.2). The adenylyl cyclase activity measured after stimulation with a guanine nucleotide or cesium fluoride did not differ between control and depressed male or female subjects. Severity of current depression and the current use of antidepressant medication were not related to the lower forskolin-stimulated enzyme activity in the depressed subjects. The difference in forskolin-stimulated adenylyl cyclase activity appears to reflect a qualitative difference in the adenylyl cyclase enzyme activity in persons with a history of major depression.

Human adenylyl cyclase type 7 contains polymorphic repeats in the 3' untranslated region: investigations of association with alcoholism.

Platelet adenylyl cyclase activity has been proposed as a trait marker for alcoholism [Tabakoff et al. (1988): N Engl J Med 318:134-13;9; Parsian et al. (1996): Alcohol Clin Exp Res 20:745-751]. Human adenylyl cyclase type 7 (ADCY7) is a member of the adenylyl cyclase gene family, and it may be the major form of adenylyl cyclase expressed in human platelets. The published cDNA sequence of ADCY7 indicated the presence of potentially polymorphic regions in the 3' untranslated region of ADCY7. PCR techniques combined with fluorescently labeled primers were used to amplify two separate tetranucleotide repeat regions [(AACA)n] in the 3' untranslated region of ADCY7 from the genomic DNA of 62 unrelated individuals. The upstream (AACA)4-repeat was not polymorphic. Five different genotypes were found in the downstream (AACA)5-7 tetranucleotide repeat region. We also tested the association of the tetranucleotide polymorphism to alcohol dependence. When 30 alcoholic and 17 control individuals were compared, no difference was found in the ADCY7 tetranucleotide polymorphism between alcohol-dependent and control groups. Nevertheless, to our knowledge these are the first polymorphisms reported in an adenylyl cyclase gene. Adenylyl cyclases are important receptor-G protein-coupled effectors and are involved in numerous neuronal functions in the central nervous system. Whether variations in ADCY7 and possible variations in other members of this gene family are underlying other psychiatric disorders remains to be studied.

A comparison of female versus male insanity acquittees in Colorado.

This study was undertaken to investigate the authors' clinical impression that there are significant differences between the male and female insanity acquittees in Colorado, and that these differences result in significantly different treatment needs. The study sample included 149 patients: 112 men and 37 women committed to the Colorado Mental Health Institute at Pueblo as not guilty by reason of insanity (NGRI). Data were collected from a computerized data system and from chart reviews. The study provides descriptive data regarding demographic, legal, and mental health parameters of these acquittees. Demographic items included prior history of incarceration, age at first arrest, type of NGRI crime committed, and severity of NGRI crime. Mental health variables included prior psychiatric hospitalization history of suicide attempts, substance abuse history, inpatient substance abuse treatment history, diagnoses, escape history and length of stay. Percentages of male and female subjects were calculated for those variables with discrete categories. Means and medians were calculated for continuous variables. Results indicate that women are significantly more likely to be given a diagnosis of mood disorder or borderline personality disorder, are significantly older than men at the time of commitment, and are statistically more likely to have committed a single violent crime than men. Men were found to have a significantly higher rate of prior and current substance abuse, a significantly higher rate of antisocial personality disorder, a significantly greater history of violent crime prior to the NGRI offense, and arrests beginning at a significantly younger age than women. Despite the higher severity of crime rating for women, their length of stay was significantly shorter than for men. The implications of the findings with regard to different treatment needs are discussed, and the findings are compared to four other studies addressing female versus male insanity acquittees in other states.