Lifetime History Of Alcohol Dependence Research Articles

CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model.

CYP2A6 (CYP2A5 in mice) is mainly expressed in the liver. Hepatic CYP2A6 expression is increased in patients with non-alcoholic fatty liver disease (NAFLD). In mice, hepatic CYP2A5 is induced by high fat diet (HFD) feeding. Hepatic CYP2A5 is also increased in monosodium glutamate-induced obese mice. NAFLD is associated with obesity. In this study, we examined whether obesity is related to CYP2A6. Obesity genetic association study: The SAGE is a comprehensive genome-wide association study (GWAS) with case subjects having a lifetime history of alcohol dependence and control subjects never addicted to alcohol. We used 1030 control individuals with self-reported height and weight. A total of 12 single nucleotide polymorphisms (SNP) within the CYP2A6 gene were available. Obesity was determined as a BMI ≥30: 30-34.9 (Class I obesity) and ≥35 (Class II and III obesity). Animal experiment study: CYP2A5 knockout (cyp2a5-/-) mice and wild type (cyp2a5+/+) mice were fed HFD for 14 weeks. Body weight was measured weekly. After an overnight fast, the mice were sacrificed. Liver and blood were collected for biochemical assays. Single marker analysis showed that three SNPs (rs8192729, rs7256108, and rs7255443) were associated with class I obesity (p < 0.05). The most significant SNP for obesity was rs8192729 (odds ratio (OR) = 1.94, 95% confidence intervals = 1.21-3.10, p = 0.00582). After HFD feeding, body weight was increased in cyp2a5-/- mice to a greater extent than in cyp2a5+/+ mice, and fatty liver was more pronounced in cyp2a5-/- mice than in cyp2a5+/+ mice. PPARα deficiency in cyp2a5-/- mice developed more severe fatty liver, but body weight was not increased significantly. CYP2A6 is associated with human obesity; CYP2A5 protects against obesity and NAFLD in mice. PPARα contributes to the CYP2A5 protective effects on fatty liver but it opposes to the protective effects on obesity.

Current Heavy Alcohol Consumption is Associated with Greater Cognitive Impairment in Older Adults

The acute consumption of excessive quantities of alcohol causes well-recognized neurophysiological and cognitive alterations. As people reach advanced age, they are more prone to cognitive decline. To date, the interaction of current heavy alcohol (ethanol [EtOH]) consumption and aging remains unclear. This study tested the hypothesis that negative consequences of current heavy alcohol consumption on neurocognitive function are worse with advanced age. Further, we evaluated the relations between lifetime history of alcohol dependence and neurocognitive function METHODS: Sixty-six participants underwent a comprehensive neurocognitive battery. Current heavy EtOH drinkers were classified using National Institute on Alcohol Abuse and Alcoholism criteria (EtOH heavy, n=21) based on the Timeline follow-back and a structured clinical interview and compared to nondrinkers, and moderate drinkers (EtOH low, n=45). Of the total population, 53.3% had a lifetime history of alcohol dependence. Neurocognitive data were grouped and analyzed relative to global and domain scores assessing: global cognitive function, attention/executive function, learning, memory, motor function, verbal function, and speed of processing. Heavy current EtOH consumption in older adults was associated with poorer global cognitive function, learning, memory, and motor function (ps<0.05). Furthermore, lifetime history of alcohol dependence was associated with poorer function in the same neurocognitive domains, in addition to the attention/executive domain, irrespective of age (ps<0.05). These data suggest that while heavy current alcohol consumption is associated with significant impairment in a number of neurocognitive domains, history of alcohol dependence, even in the absence of heavy current alcohol use, is associated with lasting negative consequences for neurocognitive function.

Genome-wide significant loci for addiction and anxiety

BackgroundPsychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. MethodsHere we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. ResultsAddiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2-q21.2, LOD=3.322) and a broad anxiety phenotype (12q24.32-q24.33, LOD=2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg=0.550–0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1-q33.2, LOD=3.054) and drug dependence-anxiety (18p11.23-p11.22, LOD=3.425). ConclusionsThis study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics.

Neurocognitive, psychiatric, and substance use characteristics in opioid dependent adults

AimsTo describe neurocognitive function among opioid-dependent adults seeking buprenorphine treatment and to explore the impact of lifetime psychiatric conditions on neurocognitive function. To explore the additive interaction of patient-based characteristics that may help to inform treatment. DesignCross-sectional assessment of neurocognitive function, substance use, and psychiatric characteristics of adults seeking buprenorphine treatment within substance use treatment centers in New York City. ParticipantsThirty-eight opioid-dependent adults seeking buprenorphine treatment. MeasurementsA comprehensive battery, which included measures of executive functioning, learning, memory, verbal fluency, attention, processing speed, and motor functioning were administered. The Wide Range Achievement Test-Third Edition, the Composite International Diagnostic Interview, and an audio computer assisted structured interview were also completed. Correlations and independent sample t-tests were used to ascertain group differences. FindingsThirty-nine percent of participants were impaired in global neurocognitive function (n=15). Over one third were impaired in either: learning (n=28), memory (n=26), executive functioning (n=17), motor functioning (n=17), attention/working memory (n=14) or verbal fluency (n=12). Lifetime history of alcohol dependence was associated with impairment in global neurocognitive, executive functioning, and motor functioning. Lifetime history of cocaine dependence was associated with impairment in executive functioning and motor functioning (all p's<0.05). Major depressive disorder history was not associated with neurocognitive impairment. ConclusionsAmong this sample of opioid-dependent adults, there were high rates of global and domain-specific neurocognitive impairment, with severe impairment in learning and memory. Lifetime alcohol and cocaine dependence were associated with greater neurocognitive impairment, particularly in executive functioning. Because executive functioning is critical for decision-making and learning/memory dysfunction may interfere with information encoding, these findings suggest that opioid-dependent adults may require enhanced support for medical decision-making.

CHRNA5 and CHRNA3 Variants and Level of Neuroticism in Young Adult Mexican American Men and Women

A lifetime history of alcohol dependence has been associated with elevations in neuroticism in Mexican American young adults. The identification of genetic markers associated with neuroticism and their influence on the development of alcohol use disorders (AUD) may contribute to our understanding of the relationship between personality traits and the increased risk of AUD in Mexican Americans. The purpose of this study was to investigate associations between neuroticism and 13 single nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine (nAChR) α5-subunit (CHRNA5) and α3-subunit (CHRNA3) genes in young adult Mexican American men and women. Participants were 465 young adult Mexican American men and women who are literate in English and are residing legally in San Diego County. Each participant gave a blood sample and completed a structured diagnostic interview. Neuroticism was assessed using the Maudsley Personality Inventory. The minor alleles of four CHRNA5 polymorphisms (rs588765, rs601079, rs680244 and rs555018) and three CHRNA3 polymorphisms (rs578776, rs6495307 and rs3743078) showed associations with neuroticism. Several of these SNPs also displayed nominal associations with DSM-IV alcohol and nicotine dependence, but tests of mediation suggested that these relations could be partially explained by the presence of co-occurring neuroticism. These findings suggest that genetic variations in nicotinic receptor genes may influence the development of neuroticism, which in turn is involved in the development of AUDs and nicotine dependence in Mexican American young adults.

Alcohol Dependence in Men: Reliability and Heritability

The assessment of a Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) life-time history of alcohol dependence (LTH-AD) has been found to be moderately reliable and substantially heritable. However, in studies of the heritability of LTH-AD, measurement error could not be discriminated from the true unique environmental effects. The aims of this study were to: (i) estimate the reliability of LTH-AD in a population based sample, (ii) identify characteristics of LTH-AD predicting a reliable diagnosis, (iii) investigate the heritability of LTH-AD as a function of diagnostic confidence, and (iv) to estimate the genetic and environmental influences on LTH-AD correcting for measurement error. An unselected sample of 4,203 male twins was interviewed twice approximately 1-year apart assessing DSM-IV LTH-AD over the same period of life. Logistic regression was used to identify clinical features that predict a reliable diagnosis LTH-AD. Genetic and environmental influences on reliable LTH-AD were examined using structural equation models. Reliability of the diagnosis of LTH-AD was moderate (κ = 0.54) and was predicted by the number of AD symptoms, treatment seeking, duration of most severe episode, and a great deal of time spent to obtain, use, or recover from alcohol use (DSM-IV AD criterion #5). Using an index of caseness, heritability of LTH-AD increased as a function of diagnostic confidence. Accounting for errors of measurement in a multivariate twin model, the heritability of LTH-AD increased from 55 to 71%. Reliably diagnosed LTH-AD can be predicted by characteristics relevant to the disorder. LTH-AD appears to be a moderately reliable disorder of high heritability.

Alcoholic Marriage: Later Start, Sooner End

Although associations between drinking behavior and marital status are well documented, timing of marital transitions as a function of alcohol use or disorder has received limited empirical attention. We examine the relationship between lifetime history of alcohol dependence (AD) and timing and survival of first marriages in a sample of 3,575 female and 1,845 male adult Australian twins born mostly between 1940 and 1964. Survival analyses were conducted using Cox proportional hazards regression models. Results indicate moderate delays in marriage associated with AD for both women and men. Among ever-married respondents, AD was strongly predictive of early separation, with similar effects observed for women and men. Heritable sources of covariation were also documented. For women, genetic influences shared between early-onset AD and marital timing were found. Genetic influences shared between AD and marital survival were observed for women without regard to onset and for men with later-onset AD. Results confirm the importance of AD as a predictor of both timing and survival of first marriages, with genetic influences contributing to observed associations.

Drinking Motives in Female Smokers: Factor Structure, Alcohol Dependence, and Genetic Influences

Alcohol and tobacco use often co-occur. Human and animal studies indicate that nicotine increases alcohol's rewarding effects and the motivation to consume it. The aims of this study were to examine whether the factorial architecture of self-reported motivations to consume alcohol differed between regular and nonregular cigarette smokers while taking into account the lifetime history of alcohol dependence and psychopathology, and to estimate the genetic and environmental influences on the motivations. Using data on 2,189 monozygotic and dizygotic female twins, we examined the factorial structure (item thresholds and factor loadings, means, and variances) of the items from the Drinking Motives Questionnaire (DMQ) in regular and nonregular smokers. Post hoc tests examined the association between the latent drinking motives factors and alcohol dependence in both groups. Twin models were fitted to the latent drinking motives factors, testing for variations in the magnitude of additive genetic, shared, and nonshared environmental influences between the groups. The 4 DMQ factors (social, conformity, coping, and enhancement) were recovered in both groups, and their measurement structure was consistent across the groups. Regular smokers reported higher levels of coping, enhancement, and social motives while nonregular smokers reported higher conformity motives. Alcohol dependence was associated with higher scores on all motives in both groups; however, in a regression analysis that included all of the motives as predictor variables, only coping was significantly related to alcohol dependence. While twin models revealed evidence for substantially greater genetic influences on enhancement (h² = 0.40), coping (h² = 0.35) and social (h² = 0.37) drinking motives in regular compared to nonregular smokers, the power to statistically distinguish the 2 groups was low. While the measurement structure of the drinking motive factors appears to be similar across regular and nonregular smokers, regular smokers report more motivation to drink for internal affect-related reasons and to obtain social reward. Of all the motives, coping was the most robust predictor of alcohol dependence in both the regular and the nonregular smokers. Further, genetic influences might play a larger role in drinking motives among regular smokers, which provides tentative evidence for latent genetic × smoking status interactions.

DSM-IV Alcohol Abuse Due to Hazardous Use: A Less Severe Form of Abuse?

A majority of individuals that meet criteria for alcohol abuse based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), do so by endorsing the hazardous use criterion. We used a large, nationally representative data set to investigate whether alcohol abuse due to hazardous use is distinct from abuse attributable to other abuse criteria and whether abuse due to hazardous use is a less severe form of alcohol abuse. Two waves of data, collected 3 years apart, from 34,653 individuals who participated in the National Epidemiological Survey on Alcohol and Related Conditions were used. Logistic regression was used to compare those with alcohol abuse due to hazardous use and those with alcohol abuse due to other criteria across several sociodemographic and psychiatric correlates at Wave 1 and across alcohol-related outcomes at the 3-year follow-up. Those with a lifetime history of alcohol dependence at Wave 1 were excluded. Abuse due to hazardous use was more commonly noted in older individuals, those not living below the poverty line, and those without nicotine dependence and was more likely to be noted in White participants. Abuse due to hazardous use was also associated with lower rates of problematic drinking, alcohol dependence, and help seeking at 3-year follow-up. Individuals endorsing hazardous use are at greater risk than those endorsing no abuse criteria, but abuse due to hazardous use may represent a less severe form of alcohol-use disorders. This is troubling, because current DSM conceptualizations allow for endorsement of hazardous use to denote alcohol-use disorders. Future classifications may wish to consider a higher threshold for alcohol-use disorders, particularly when hazardous use is endorsed.

Use of Clergy Services among Individuals Seeking Treatment for Alcohol Use Problems

This study examined the prevalence and characteristics of adults with an alcohol use-related problem who receive clergy services. Data come from the National Epidemiologic Survey on Alcohol and Related Conditions. Among persons who sought any services for alcohol-related problems (n = 1,910), 14.7% reported using clergy services. In a multivariable logistic regression model, factors associated with increased likelihood of service use included being Black, aged 35-54 years, a lifetime history of alcohol dependence, major depressive disorder, and personality disorder. Clergy may benefit from training to identify alcohol use problems and serve an important role in making treatment referrals.

Effects of a Diagnosis or Family History of Alcoholism on the Taste Intensity and Hedonic Value of Sucrose

Given inconsistent findings in published studies, we examined whether a personal lifetime history of alcohol dependence (AD) or a parental history of alcoholism affected preference for sweet solutions. Ninety-three alcohol-dependent subjects rated the intensity and hedonic value of five different sucrose solutions, which was compared with similar data from 122 subjects screened to exclude alcohol dependence. The effect of a family history of alcoholism (FH) was examined in the AD group. Neither the diagnosis of AD nor a family history of alcoholism was associated with ratings of sweetness intensity or sweet preference. These findings do not support the hypothesis that sucrose preference is positively associated with either a personal lifetime history of AD or a family history of alcoholism.

Diagnosing alcohol abuse in alcohol dependent individuals: Diagnostic and clinical implications

In DMS-IV, the diagnosis of alcohol abuse is precluded by the diagnosis of alcohol dependence. The goal of this study was to examine the diagnostic and clinical implications of diagnosing alcohol abuse among alcohol dependent individuals. Treatment-seeking psychiatric outpatients with a lifetime history of alcohol dependence ( n = 544), some of whom ( n = 45) did not meet lifetime criteria for alcohol abuse completed in-depth, face-to-face, semi-structured clinical assessments of DSM-IV axis I and axis II psychopathology. Alcohol dependent patients who did not meet criteria for alcohol abuse were significantly more likely to be female, have a later age of onset for alcohol dependence, have fewer dependence symptoms, and have a lower rate of positive family history for alcoholism, and were less likely to report a lifetime history of DSM-IV drug use disorders and PTSD. These findings suggest that diagnosing alcohol abuse among alcohol dependent patients may be clinically useful as an index of severity and higher likelihood of comorbid drug abuse and dependence. Future studies are needed to establish whether these differences are clinically significant in terms of the course of the disorder and response to treatment.

Alcohol dependence and reproductive onset: findings in two Australian twin cohorts.

Although early alcohol use is a strong predictor of future alcohol problems and adolescent drinking is associated with risky sexual behavior predictive of early childbearing, reproductive dysfunctions associated with delayed childbearing have been reported in adult drinkers. We examine the relationship between lifetime history of alcohol dependence (AD) and timing of first childbirth across reproductive development. Data were drawn from two cohorts of Australian twins born between 1893 and 1964 (3634 female and 1880 male twins) and between 1964 and 1971 (3381 female and 2748 male twins). Survival analyses were conducted using Cox proportional hazards regression models predicting age at first childbirth from AD, with sociodemographic characteristics, regular smoking, history of psychopathology, and family and childhood risks included as control variables in adjusted models. Results suggest alcoholic women in both cohorts show overall delayed reproduction, with little effect of AD on timing of first reproduction in men. Effects of AD are particularly strong for women in the older cohort, where AD is associated with 73% decreased likelihood of first childbirth after age 29 [hazard ratio (HR) = 0.27, 95% CI: 0.10-0.75]. In adjusted models, effects reduce only slightly (HR = 0.29, 95% CI: 0.11-0.80). For women in the young cohort, AD is associated with delayed reproduction after age 24, with 40% decreased likelihood of first childbirth (HR = 0.60, 95% CI: 0.48-0.75). AD remains predictive in adjusted models, but without age interaction (HR = 0.72, 95% CI: 0.62-0.85). Findings of delayed reproductive onset in alcoholic women are consistent with alcohol-related reproductive dysfunctions, although underlying mechanisms remain largely unknown. To better understand AD differences in reproductive onset, continued research on both biological and psychosocial risks is needed.

The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies

Serotonin Transporter (5HTT or SLC6A4) mRNA transcription is regulated by both genetic and epigenetic mechanisms. Unfortunately, despite intense scrutiny, the exact identity and contribution of each of these regulatory mechanisms, and their relationship to behavioral illness remain unknown. This lack of knowledge is critical because alterations in SLC6A4 function are posited to be central to a wide variety of CNS disorders. In order to address this shortcoming, we quantified 5HTTLPR genotype, SLC6A4 mRNA production and CpG methylation using biomaterial from 192 lymphoblast cell lines derived from subjects who participated in the latest wave of the Iowa Adoption Studies. We then analyzed the resulting data with respect to clinical characteristics. We confirmed prior findings that the short (s) 5HTTLPR allele is associated with lower amounts of mRNA transcription, but there was no significant effect of the "Long G" allele on mRNA transcription. We also found that CpG methylation was higher (P < 0.0008) and mRNA production (P < 0.0001) was lower in females as compared to males. Those subjects with a lifetime history of Alcohol Dependence had higher levels of SLC6A4 mRNA. There was a trend for an association of increased overall methylation with lifetime history of major depression. Finally, we confirm our prior findings that the exact levels of 5HTT mRNA expression are dependent on how it is measured. We conclude that both genetic variation and epigenetic modifications contribute to the regulation of SLC6A4 function and that more in-depth studies of the molecular mechanisms controlling gene activity and the relationship of these mechanisms to behavioral illness are indicated.

Maintaining Abstinence in a Northern Plains Tribe

In this article, we examine how American Indian individuals with a history of alcohol dependence have been able to maintain their abstinence despite strong pressures to return to drinking. This work builds on close collaboration with individual tribal members who have resolved their problems with alcohol and community-based service providers to develop open-ended qualitative interviews. Using these, we explored how former drinkers respond to the twin challenges raised by their former drinking associates and strong feelings that emerge when alcohol is no longer an option for coping with life's difficulties. The resolution of these challenges is central to abstinence, given the strong ties between drinking and sociality in some American Indian communities (including the one where this study was conducted) and underscores the ways in which alternate relations to alcohol can be established even within a heavy drinking cultural context. Interviews were conducted with 133 individuals from a northern plains tribe who were identified in a previous epidemiological study as having a lifetime history of alcohol dependence. Inquiry into the processes involved in the meaningful constitution of abstinence for these men and women highlights the role of religion and spirituality for some, but by no means all of these individuals and, more broadly, the emergence of what Bea Medicine has characterized as "new ways of coping," which force us to expand on leading conceptualizations of coping in the literature on problems with alcohol.

Problematic eating and feeding behaviors of 36‐month‐old children

We incorporated selected items from several existing instruments to create a comprehensive multifactorial instrument to measure problematic eating behaviors in young children and to examine the prevalences and correlates of these behaviors. A community sample of young mothers (N = 93) completed the inventory of problematic eating behaviors for their 36-month-old children. The most common child problems reported by mothers were the spitting out of food during feedings and becoming upset when food was restricted. A four-factor solution identified pickiness (e.g., child eats a limited variety of food), food refusal (e.g., child refuses to eat specific foods), struggle for control (e.g., frequent struggles with child over food), and positive parental behavior (e.g., praising child about his/her food intake) domains. Internal consistency was moderate to good for all factors. Only the struggle for control factor was related to other problematic behaviors as measured by the Child Behavior Check List (CBCL). The food refusal factor was related to mothers' lifetime history of any psychopathology. The pickiness factor was related to mothers' lifetime history of alcohol dependence. Findings suggest that child clinicians should be sensitive to the quality of mother-child interactions during feeding.

Relationships Between Effects of Smoking, Gender, and Alcohol Dependence on Platelet Monoamine Oxidase-B: Activity, Affinity Labeling, and Protein Measurements

Background Many studies have reported apparent associations between platelet monoamine oxidase (MAO) activity and susceptibility to alcoholism and other psychiatric conditions. Alcohol-dependent individuals generally exhibit lower platelet MAO activity compared with controls, and on this basis, platelet MAO has been proposed as a potential genetic marker for predisposition to alcoholism. However, several lines of evidence also suggest that MAO activity is reduced in both the brain and platelets of smokers. Many alcohol-dependent individuals are also tobacco users, and few studies have attempted to dissociate the effect of alcohol and tobacco use on MAO activity. Methods Platelet MAO-B activity in 629 subjects recruited as part of the WHO/ISBRA Study of State and Trait Markers of Alcohol Use and Dependence was assayed by using a high throughput fluorescence assay. Platelet MAO-B protein concentrations were measured by analysis of immunoblots probed with a polyclonal antibody selective for MAO. Quantitative measurements of affinity labeling of platelet MAO were made by using the selective MAO-B catalytic site antagonist [3H]Ro 19–6327. Results Multiple regression analysis revealed that subjects’ gender, cigarette smoking, lifetime alcohol dependence, and recruitment site each contributed independently to the variance in platelet MAO activity levels. Female subjects had significantly higher MAO activity levels than males, whereas heavy smokers had significantly lower MAO activity levels than nonsmokers. Immunoblot measurement of platelet MAO-B protein demonstrated that females had significantly higher MAO-B protein concentrations. Platelet MAO-B protein concentrations did not differ significantly between smokers and nonsmokers but were lower in subjects with a diagnosis of lifetime alcohol dependence (DSM-IV) compared with subjects who were never alcohol dependent. Measurements of affinity labeling by [3H]Ro 19–6327 of platelet MAO correlated significantly with MAO activity levels (i.e., the lower MAO-B activity in smokers was mirrored by lower levels of [3H]Ro 19–6327 binding). Conclusions In this international population, gender, cigarette smoking, lifetime history of alcohol dependence, and recruitment site were associated with lower platelet MAO activity levels. Differences in MAO activity associated with gender and lifetime alcohol dependence can be attributed largely to differences in MAO-B protein concentration, whereas those associated with smoking behavior may be the result of binding of an inhibitor contained in cigarette smoke to platelet MAO-B at catalytic site of MAO.

Relationships Between Effects of Smoking, Gender, and Alcohol Dependence on Platelet Monoamine Oxidase‐B: Activity, Affinity Labeling, and Protein Measurements

Many studies have reported apparent associations between platelet monoamine oxidase (MAO) activity and susceptibility to alcoholism and other psychiatric conditions. Alcohol-dependent individuals generally exhibit lower platelet MAO activity compared with controls, and on this basis, platelet MAO has been proposed as a potential genetic marker for predisposition to alcoholism. However, several lines of evidence also suggest that MAO activity is reduced in both the brain and platelets of smokers. Many alcohol-dependent individuals are also tobacco users, and few studies have attempted to dissociate the effect of alcohol and tobacco use on MAO activity. Platelet MAO-B activity in 629 subjects recruited as part of the WHO/ISBRA Study of State and Trait Markers of Alcohol Use and Dependence was assayed by using a high throughput fluorescence assay. Platelet MAO-B protein concentrations were measured by analysis of immunoblots probed with a polyclonal antibody selective for MAO. Quantitative measurements of affinity labeling of platelet MAO were made by using the selective MAO-B catalytic site antagonist [3H]Ro 19-6327. Multiple regression analysis revealed that subjects' gender, cigarette smoking, lifetime alcohol dependence, and recruitment site each contributed independently to the variance in platelet MAO activity levels. Female subjects had significantly higher MAO activity levels than males, whereas heavy smokers had significantly lower MAO activity levels than nonsmokers. Immunoblot measurement of platelet MAO-B protein demonstrated that females had significantly higher MAO-B protein concentrations. Platelet MAO-B protein concentrations did not differ significantly between smokers and nonsmokers but were lower in subjects with a diagnosis of lifetime alcohol dependence (DSM-IV) compared with subjects who were never alcohol dependent. Measurements of affinity labeling by [3H]Ro 19-6327 of platelet MAO correlated significantly with MAO activity levels (i.e., the lower MAO-B activity in smokers was mirrored by lower levels of [3H]Ro 19-6327 binding). In this international population, gender, cigarette smoking, lifetime history of alcohol dependence, and recruitment site were associated with lower platelet MAO activity levels. Differences in MAO activity associated with gender and lifetime alcohol dependence can be attributed largely to differences in MAO-B protein concentration, whereas those associated with smoking behavior may be the result of binding of an inhibitor contained in cigarette smoke to platelet MAO-B at catalytic site of MAO.

Platelet Adenylyl Cyclase Activity as a Trait Marker of Alcohol Dependence

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. 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. 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. 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.

Platelet Adenylyl Cyclase Activity as a Trait Marker of Alcohol Dependence

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, γ-glutamyltransferase, aspartate aminotransferase, serum carbohydrate-deficient transferrin (CDT), and urinary5-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.