Showing papers in "Alcoholism: Clinical and Experimental Research in 2000"

Integrating Person-Centered and Variable-Centered Analyses: Growth Mixture Modeling With Latent Trajectory Classes

Abstract: Background: Many alcohol research questions require methods that take a person-centered approach because the interest is in finding heterogeneous groups of individuals, such as those who are susceptible to alcohol dependence and those who are not. A person-centered focus also is useful with longitudinal data to represent heterogeneity in developmental trajectories. In alcohol, drug, and mental health research the recognition of heterogeneity has led to theories of multiple developmental pathways. Methods: This paper gives a brief overview of new methods that integrate variable- and person-centered analyses. Methods discussed include latent class analysis, latent transition analysis, latent class growth analysis, growth mixture modeling, and general growth mixture modeling. These methods are presented in a general latent variable modeling framework that expands traditional latent variable modeling by including not only continuous latent variables but also categorical latent variables. Results: Four examples that use the National Longitudinal Survey of Youth (NLSY) data are presented to illustrate latent class analysis, latent class growth analysis, growth mixture modeling, and general growth mixture modeling. Latent class analysis of antisocial behavior found four classes. Four heavy drinking trajectory classes were found. The relationship between the latent classes and background variables and consequences was studied. Conclusions: Person-centered and variable-centered analyses typically have been seen as different activities that use different types of models and software. This paper gives a brief overview of new methods that integrate variable- and person-centered analyses. The general framework makes it possible to combine these models and to study new models serving as a stimulus for asking research questions that have both person- and variable-centered aspects.

Neurocognitive functioning of adolescents: effects of protracted alcohol use.

Abstract: Background: The present study examined associations between alcohol involvement in early to middle adolescence and neuropsychological (NP) functioning. Methods: Alcohol-dependent adolescents (n= 33) with over 100 lifetime alcohol episodes and without dependence on other substances were recruited from alcohol/drug abuse treatment facilities. Comparison (n= 24) adolescents had no histories of alcohol or drug problems and were matched to alcohol-dependent participants on age (15 to 16 years), gender, socioeconomic status, education, and family history of alcohol dependence. NP tests and psychosocial measures were administered to alcohol-dependent participants following 3 weeks of detoxification. Results: Alcohol-dependent and comparison adolescents demonstrated significant differences on several NP scores. Protracted alcohol use was associated with poorer performance on verbal and nonverbal retention in the context of intact learning and recognition discriminability. Recent alcohol withdrawal among adolescents was associated with poor visuospatial functioning, whereas lifetime alcohol withdrawal was associated with poorer retrieval of verbal and nonverbal information. Conclusions: Deficits in retrieval of verbal and nonverbal information and in visuospatial functioning were evident in youths with histories of heavy drinking during early and middle adolescence.

Binge ethanol consumption causes differential brain damage in young adolescent rats compared with adult rats.

Abstract: Background: Adolescents respond differently to alcohol than adults. Furthermore, binge drinking in young adolescents is becoming increasingly common. Methods: To determine if the effects of binge drinking on brain damage are different in juveniles compared with adults, the effects of a 4 day binge ethanol treatment (e.g., 4 days of 4 times per day 15% ethanol intragastrically, approximately 9–10 g/kg/day ethanol) were investigated in adolescent-juvenile rats (JVN) 35 days old and compared with adult (ADT) rats 80 to 90 days old. Brain damage was measured by using the amino cupric silver stain of de Olmos et al. (1994). Results: Significant brain damage was found in both groups. The olfactory bulbs were equally damaged in both groups; however, the associated frontal cortical olfactory regions were damaged only in JVN. The anterior portions of the piriform and perirhinal cortices also were damaged only in JVN rats. Quantitation of silver-stained frontal areas in binge ethanol-treated JVN rats ranged from 400% to 1260% of control values. For example, in anterior perirhinal cortex, silver stain increased from 48 ± 14 to 444 ± 114 (mm2× 103 argyrophilic area;p < 0.01) in JVN control and binge ethanol-treated animals, respectively. In contrast, posterior perirhinal cortex showed greater damage in adults, being 236 ± 76 vs. 875 ± 135 (mm2× 103 argyrophilic area;p < 0.005) in JVN and ADT, respectively. Conclusions: The young-adolescent brain shows differential sensitivity to alcohol-induced brain damage compared with adults.

Pattern of Motor and Cognitive Deficits in Detoxified Alcoholic Men

Abstract: Background: Chronic excessive consumption of alcohol produces marked deficits in cognitive and motor abilities, although not all functions are affected to the same extent. Furthermore, although the occurrence of neuropsychological deficits in recently detoxified alcoholics is firmly established, the relative severity of these deficits, the specific neural systems that underlie the deficits, and their relationship to age and alcohol consumption variables either are less established or have proven elusive altogether. Methods: We administered an extensive battery of neuropsychological tests, chosen for their known sensitivity to brain lesions in specific locations, to 71 recently (1 month) detoxified alcoholic men and 74 healthy controls who spanned the adult age range. Test scores were standardized to the controls for age and grouped a priori into composites that reflected performance in six functional domains: executive functions, short-term memory, upper limb motor ability, declarative memory, visuospatial abilities, and gait and balance. Analogous verbal and nonverbal materials and left- and right-hand upper limb motor tasks were used to test whether alcohol-related deficits were greater for left or right hemisphere. Results: Compared with controls, the alcoholics were impaired on executive functions, visuospatial abilities, and gait and balance even after we accounted for group differences in estimated premorbid IQ and education. Within the alcoholic group, the most salient deficits were in gait and balance and visuospatial abilities. No consistent lateralized deficit was observed across the four domains tested. Unlike the cognitive composites, the upper limb motor ability and gait and balance composites both showed increasing vulnerability to age, with an independent contribution to the gait and balance dysfunction from the amount of alcohol consumed over a lifetime. Conclusions: The pattern of functional deficits implicates at least two principal neural systems: the cerebellar-frontal system and the corticocortical system between the prefrontal and parietal cortices. In addition, age and amount of alcohol consumption were better predictors of motor than cognitive impairments.

Gene expression in human alcoholism: microarray analysis of frontal cortex.

Abstract: Background: Changes in brain gene expression are thought to be responsible for the tolerance, dependence, and neurotoxicity produced by chronic alcohol abuse, but there has been no large scale study of gene expression in human alcoholism. Methods: RNA was extracted from postmortem samples of superior frontal cortex of alcoholics and nonalcoholics. Relative levels of RNA were determined by array techniques. We used both cDNA and oligonucleotide microarrays to provide coverage of a large number of genes and to allow cross-validation for those genes represented on both types of arrays. Results: Expression levels were determined for over 4000 genes and 163 of these were found to differ by 40% or more between alcoholics and nonalcoholics. Analysis of these changes revealed a selective reprogramming of gene expression in this brain region, particularly for myelin-related genes which were downregulated in the alcoholic samples. In addition, cell cycle genes and several neuronal genes were changed in expression. Conclusions: These gene expression changes suggest a mechanism for the loss of cerebral white matter in alcoholics as well as alterations that may lead to the neurotoxic actions of ethanol.

Early adult outcomes of adolescent binge drinking: person- and variable-centered analyses of binge drinking trajectories.

Abstract: BACKGROUND: Many studies of the consequences of binge drinking take a variable-centered approach that may mask developmentally different trajectories. Recent studies have reported qualitatively different binge drinking trajectories in young adulthood. However, analyses of developmental trajectories of binge drinking have not been examined for an important period of drinking development: adolescence. The purpose of this study was to examine young adult outcomes of adolescent binge drinking using an approach that combines person-centered and variable-centered methods. METHODS: Data were from the Seattle Social Development Project, an ethnically diverse, gender balanced sample (n = 808) followed prospectively from age 10 to age 21. Semiparametric group-based modeling was used to determine groups of binge drinking trajectories in adolescence. Logistic regression was used to examine how well the trajectory groups predicted young adult outcomes after demographics, childhood measures, and adolescent drug use were considered. RESULTS: Four distinct trajectories of binge drinking during adolescence were identified: Early Highs, Increasers, Late Onsetters, and Nonbingers. These trajectories significantly predicted positive and negative outcomes in adulthood after controlling for demographic characteristics, early proxy measures of the outcome, and adolescent drug use. CONCLUSIONS: This integrated person- and variable-centered approach provides more information about the effects of specific patterns of binge drinking than studies that employ variable-centered methods alone. Language: en

In vivo detection and functional correlates of white matter microstructural disruption in chronic alcoholism.

Abstract: Background: Postmortem studies report degradation of brain white matter microstructure in chronic alcoholism, but until recently, in vivo neuroimaging could provide measurement only at a macrostructural level. The development of magnetic resonance diffusion tensor imaging (DTI) for clinical use offers a method for depicting and quantifying the diffusion properties of white matter expressed as intravoxel and intervoxel coherence of tracts and fibers. Methods: This study used DTI to examine the intravoxel coherence measured as fractional anisotropy (FA) and intervoxel coherence (C) of white matter tracts of the genu and splenium of the corpus callosum and of the centrum semiovale in 15 detoxified alcoholic men and 31 nonalcoholic control subjects. Exploratory correlational analyses examined the relationships between regional DTI measures and tests of attention and working memory in the alcoholic patients. Results: The alcoholic group had lower regional FA than the control group. C was lower in the alcoholics than controls in the splenium only. Working memory correlated positively with splenium FA, whereas attention correlated positively with genu C. Conclusions: These results provide in vivo evidence for disruption of white matter microstructure in alcoholism and suggest that interruption of white matter fiber coherence contributes to disturbance in attention and working memory in chronic alcoholism.

Blunted stress cortisol response in abstinent alcoholic and polysubstance-abusing men.

Abstract: Background: This study tested cortisol responses to a psychological stressor in controls (CT) versus patients who were diagnosed as alcohol dependent (AD) or alcohol and stimulant dependent (ADSD) by DSM-IV criteria and who were abstinent for 3 to 4 weeks from alcohol and illicit drugs. Alcohol increases cortisol secretion acutely and during withdrawal. However, there is little information about abnormalities of hypothalamic-pituitary-adrenocortical (HPA) reactivity in recovering alcoholics. Methods: Accordingly, we tested HPA function in the laboratory between 7:00 and 9:30 AM on control versus stress days. Stress consisted of a 20-min public speaking challenge with preparation and delivery of two short speeches, ostensibly evaluated for quality of delivery, whereas control involved relaxing for the same period. Cortisol was measured in saliva collected at baseline, stress or control, and recovery period, and also at home at 9:00 PM on one of the two days. Results: The three groups did not differ in diurnal patterns of cortisol secretion on the rest day and 9:00 PM sample, which indicated that AD and ADSD patients had intact diurnal HPA regulation at rest. During speech stress, the CT subjects showed the expected cortisol increase (p < 0.0001), whereas neither AD nor ADSD patients responded significantly. Cortisol values were not accounted for by covariates such as depression, posttraumatic stress disorder, glucose metabolism, or anthropometric or demographic characteristics. Conclusions: The apparent stress hyporesponsiveness of the AD and ADSD patients suggests a persistent disruption of HPA function, perhaps due to incomplete recovery from prior abuse, or to a preexisting alteration in neural systems that regulate HPA responses to stress.

Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping.

Abstract: Background There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. Methods: AdditionaLgenotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-111-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets.

Skeletal response to alcohol.

Abstract: This review briefly assesses the well-established effects of alcohol consumption on bone and mineral metabolism and addresses areas of controversy that need additional research Alcohol consumption is a risk factor for osteoporosis based on the frequent finding of a low bone mass, decreased bone formation rate, and increased fracture incidence in alcoholics Alcohol also has been shown to reduce bone formation in healthy humans and animals and to decrease proliferation of cultured osteoblastic cells On the other hand, it has been difficult to demonstrate alcohol-induced bone loss and increased fracture rate in population-based studies Indeed, most population-based studies have shown a positive association between alcohol and bone mass and no change or a decrease in fracture risk Overall, the evidence generally supports a detrimental effect of chronic alcohol abuse on the skeleton of men and a neutral or generally beneficial effect of light to moderate alcohol consumption, especially in older women This latter putative beneficial effect may be due to a reduction in the age-related increase in bone remodeling associated with postmenopausal bone loss Specific areas of research are recommended to clarify the dose and sex effects of alcohol consumption and to determine cellular and molecular mechanisms of action The goals of this proposed research emphasis are to determine the degree of risk for the range of alcohol consumption, to set guidelines of consumption compatible with maintaining bone health, and to develop appropriate countermeasures to prevent or reverse the detrimental skeletal effects of alcohol abuse

Decision-Making Biases, Antisocial Personality, and Early-Onset Alcoholism

Abstract: Background: Disinhibited, antisocial traits increase the risk for early-onset alcoholism. Research also suggests that decision biases which favor immediate large rewards regardless of long-term consequences may be important mechanisms associated with the biological substrates of antisocial traits. This study tested the hypothesis that early-onset alcoholism with antisocial personality (ASP) would be associated with favoring immediate larger rewards despite their being associated with long-term losses. Methods: Twenty-seven early-onset alcoholics with and without a diagnosis of ASP, eight subjects with ASP but no alcohol dependence, and 32 controls were tested on a task that manipulated the magnitude of immediate rewards and the magnitude of long-term punishments. The sample was recruited from the community via advertisements. Results: Compared with subjects without ASP, subjects with ASP favored larger immediate rewards despite long-term losses regardless of alcohol dependence; however, they learned to shift their decisions in a more advantageous direction over time. A disadvantageous decision bias also was associated with drinking greater quantities of alcohol and having a lower IQ. Conclusions: This study suggests that ASP in a young adult noninstitutionalized sample was associated with a pattern of disadvantageous decision making similar to that observed in patients with antisocial behavioral characteristics associated with lesions in the ventromedial frontal cortex. The data also suggest that this pattern of disadvantageous decision making is associated with consuming larger quantities of alcohol but not consuming alcohol more frequently.

Binge pattern ethanol exposure in adolescent and adult rats: differential impact on subsequent responsiveness to ethanol.

Abstract: Background: Recent evidence indicates that adolescent animals are more sensitive than adults to the disruptive effects of acute ethanol exposure on spatial learning. It is not yet known whether adolescent animals are also more sensitive than adults to the enduring neurobehavioral effects of repeated ethanol exposure. In this study, animals were exposed to ethanol in a binge-pattern during either adolescence or adulthood. At a time when all subjects were adults, spatial working memory was examined in the absence and presence of an acute ethanol challenge. Methods: Rats were exposed to ethanol (5.0 g/kg intraperitoneally) or isovolumetric saline at 48 hr intervals over 20 days. Exposure began on either postnatal day 30 (adolescent group) or 70 (adult group). Twenty days after the final injection, a time at which all animals were adults, the subjects were tested on an elevated plus maze and then were trained to perform a spatial working memory task on an eight-arm radial maze. At the beginning of each session of training on the working memory task, subjects retrieved food rewards on four of the eight arms. After a delay, subjects were placed on the maze and allowed to retrieve food from the remaining four arms. Results: Prior exposure to ethanol did not influence behavior on the plus maze. Performance of the groups did not differ during acquisition of the spatial working memory task with a 5 min delay or during subsequent testing with a 1 hr delay. However, animals treated with ethanol during adolescence exhibited larger working memory impairments during an ethanol challenge (1.5 g/kg intraperitoneally) than subjects in the other three groups. Conclusions: The findings indicate that binge pattern exposure to ethanol during adolescence enhances responsiveness to the memory-impairing effects of ethanol in adulthood.

Evidence of a structural effect for alcohol outlet density: a multilevel analysis.

Abstract: BACKGROUND: Ecological studies reveal that alcohol-related outcomes tend to occur in high alcohol outlet density neighborhoods. The ecological design of these studies limits the interpretation of the findings in terms of the level of the effect. The effect of alcohol outlet density could be related to greater individual access to alcohol, an individual level effect, or to the grouping of drinkers by neighborhood, a structural effect at the neighborhood level. METHODS: To differentiate between individual and neighborhood level possibilities, we conducted a multilevel study. Individual distance to the closest alcohol outlet was the individual level measure of the effect of alcohol outlet density, whereas the mean distance to the closest alcohol outlet for all individuals within a census tract was the neighborhood level measure for the effect of alcohol outlet density. We analyzed telephone surveys of 2604 telephone households within 24 census tracts stratified by poverty status and alcohol outlet density. Individual distance to alcohol outlets, age, sex, race/ethnicity, and level of education were entered as individual level covariates, and their corresponding aggregated means were entered as census tract level covariates (i.e., mean distance to outlets, mean age, percentage male, percentage Black, mean education). RESULTS: Analysis of variance revealed that 16.2% of the variance in drinking norms and 11.5% of the variance in alcohol consumption were accounted for at the census tract level. In multivariate hierarchical analysis, individual distance to the closest alcohol outlet was unrelated with drinking norms and alcohol consumption, whereas mean distance to the closest alcohol outlet demonstrated a negative relation with drinking norms (betae = -5.50+/-2.37) and with alcohol consumption (betae = -0.477+/-0.195); that is, the higher the mean distance to the closest alcohol outlet, the lower the mean drinking norms score and mean level of alcohol consumption. CONCLUSIONS: The findings suggest that the effect of alcohol outlet density on alcohol-related outcomes functions through an effect at the neighborhood level rather than at the individual level. Problem drinkers tend to be grouped in neighborhoods, an effect predicted by alcohol outlet density. Language: en

Chronic Daily Ethanol and Withdrawal: 1. Long‐Term Changes in the Hypothalamo‐Pituitary‐Adrenal Axis

Abstract: Background: Hypothalamo-pituitary-adrenal (HPA) function has been demonstrated to be compromised for weeks and even months after alcoholics cease ethanol consumption. Because nonalcoholic subjects with family history-associated increased risk for alcoholism also exhibit compromised HPA function, it is not clear whether defects in the HPA axis of abstinent alcoholics reflect a preexisting condition that may be responsible for increased risk for alcohol abuse versus a persisting adaptational change in response to prolonged alcohol abuse. Consequently, we investigated whether chronic daily ethanol consumption and withdrawal by male Sprague Dawley® rats would induce persistent HPA changes consistent with those demonstrated in abstinent alcoholics. Methods and Results: In an initial experiment in which ethanol (5%, w/v) was incrementally introduced to liquid diet over a 1 week period followed by 4 weeks of chronic ethanol consumption, not only ethanol-treated rats but also pair-fed control rats exhibited decreased (p < 0.05 vs. ad-libitum-fed controls) anterior pituitary pro-opiomelanocortin (POMC) mRNA concentrations and associated decreases in plasma corticosterone and adrenocorticotropin (ACTH) levels for at least 3 weeks after gradual withdrawal of ethanol from the diet. Pair-feeding-induced decreases (p < 0.05) in thymus and spleen weights suggested that the pair-fed controls were likely stressed in this model, probably in response to the marked and irregular suppression of liquid diet consumption immediately after introduction of ethanol. Consequently, a second model was developed in which ethanol was introduced to the liquid diet much more gradually (i.e., over 3 weeks). In contrast with the rapid ethanol-introduction model, this more prolonged ethanol introduction followed by 4 weeks of chronic daily ethanol consumption increased plasma corticosterone levels (p < 0.05), increased adrenal gland weight (p < 0.05), and decreased thymus and spleen weights (both p < 0.01) without altering any of these parameters in the pair-fed controls. Three weeks after gradual withdrawal of ethanol from the diet, anterior pituitary POMC mRNA concentrations were suppressed (p < 0.05) and thymus and spleen weights were increased (p < 0.05) versus both pair-fed and ad-libitum-fed controls, accompanied by trends for decreased basal plasma corticosterone and adrenal weights. Conclusions: Chronic daily ethanol treatment induced changes in the HPA axis that persisted for at least 3 weeks after complete cessation of ethanol consumption. These persistent alterations in the HPA axis are similar to the aberrant HPA regulation of abstinent alcoholics, sons of alcoholics, Lewis rats, and individuals who suffer from posttraumatic stress disorder and some types of depression, that is, categories of individuals who all exhibit increased risk for high ethanol consumption. Thus, these chronic daily ethanol-induced persistent changes in the HPA axis may have significant roles in alcohol abstinence syndrome and may increase vulnerability to relapse.

Reliability and validity of the Alcohol Use Disorders Identification Test (AUDIT) imbedded within a general health risk screening questionnaire: results of a survey in 332 primary care patients.

Abstract: Background: Self-administered, general health risk screening questionnaires that are administered while patients wait in the doctor's office may be a reasonable and timesaving approach to address the requirements of preventive medicine in a typical 10-min medical visit. The psychometric characteristics of the Alcohol Use Disorders Identification Test (AUDIT) incorporated within a health questionnaire (H-AUDIT) have not been examined. Methods: The reliability and validity of the self-administered AUDIT were compared between the H-AUDIT and the AUDIT used as a single scale (S-AUDIT) in 332 primary care patients. Results: No major demographic or alcohol use characteristics were found between the 166 subjects who completed the H-AUDIT and the 166 individuals who completed the S-AUDIT. The test-retest reliability of the 166 subjects who completed the H-AUDIT [estimated by Spearman correlation coefficient at a 6-week interval (0.88), internal consistency (total correlation coefficients for all items ranged from 0.38 to 0.69; Cronbach α index 0.85), and the sensitivity and specificity of the H-AUDIT were used to identify at-risk drinkers’ areas under receiver operating characteristic (0.77) and alcohol-dependent subjects’ areas under receiver operating characteristic (0.89)] was similar to the same measurements obtained with the 166 individuals who completed the S-AUDIT. Conclusions: The AUDIT incorporated in a health risk screening questionnaire is a reliable and valid self-administered instrument to identify at-risk drinkers and alcohol-dependent individuals in primary care settings.

Predictors of substance abuse treatment retention among women and men in an HMO.

Abstract: Background: Although prior research has examined predictors of treatment retention in public alcohol and drug treatment programs, little is known about factors that influence treatment retention in an insured outpatient population Because there is growing evidence that the factors which influence treatment retention may differ by gender, we identify sex-specific predictors Methods: We recruited all eligible intakes to a health maintenance organization's outpatient alcohol and drug treatment program during a 2-year period and obtained a sample of 317 women and 599 men The programs, day hospital and traditional outpatient modalities, were abstinence based We separated our sample by sex and used least squares and logistic regression to identify independent predictors of length of stay and program completion, respectively Results: One general pattern of predictors of increased retention was shared by women and men in this alcohol and drug treatment program—fewer and less severe drug problems However, most predictors were sex-specific Among women, retention was predicted by having higher incomes, belonging to ethnic categories other than African American, being unemployed, being married, and having lower levels of psychiatric severity Among men, predictors of higher retention included being older, receiving employer suggestions to enter treatment, and having abstinence goals Conclusions: These findings highlight the importance of examining aspects of the course of treatment separately by sex They also suggest treatment factors that may enhance retention among insured populations, including employer referrals, psychiatric services, and drug-related services

Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype.

Abstract: Background: Characteristic behaviors of some alcohol-dependent individuals, e.g., binge drinking, comorbid psychopathology, and some types of alcohol-related problems, have been linked to abnormalities in serotonergic neurotransmission. However, studies that have evaluated serotonergic pharmacotherapy for reducing drinking have yielded conflicting results. One explanation for these findings is a general failure to distinguish alcohol subgroups that may be differentiated on the basis of serotonergic abnormalities. However, in 1996, Kranzler and colleagues reported that Type B alcoholics, who are characterized by high levels of premorbid vulnerability, alcohol dependence severity, and comorbid psychopathology, showed less favorable drinking outcomes in response to treatment with fluoxetine, a serotonin reuptake inhibitor, than with placebo. This medication effect was not seen in Type A alcoholics, i.e., those with lower risk/severity of alcoholism and psychopathology. The aim of the present study was to explore the validity of differential responding by alcohol-dependent subtypes using the serotonin reuptake inhibitor, sertraline. Methods: A k-means clustering procedure was applied to a sample of alcohol-dependent subjects enrolled in a 14-week, placebo-controlled trial of 200 mg/day of sertraline, classifying them into lower-risk/severity (Type A: n= 55) and higher-risk/severity (Type B: n= 45) subgroups. Results: A significant interaction between alcoholic subtype and medication condition was found, confirming the findings of Kranzler and colleagues that alcoholic subtypes responded differentially to serotonergic medication. Somewhat at variance with their results, however, the present study showed that the lower risk/severity (Type A) subjects had more favorable outcomes when treated with sertraline compared to placebo. Conclusions: Alcoholic subtypes differentially responded to sertraline when used as a treatment to reduce alcohol drinking, with one subtype having more favorable outcomes. Subtyping alcoholics may help to resolve conflicting findings in the literature on serotonergic treatment of alcohol dependence.

Ability of Baclofen in Reducing Alcohol Craving and Intake: II—Preliminary Clinical Evidence

Abstract: Background Accumulating evidence shows the efficacy of the y-aminobutyric acid (GABA,) receptor agonist baclofen in reducing alcohol intake in rats, but no studies have been performed in alcoholics. In the present preliminary study we investigated the effect of short-term baclofen administration on craving for alcohol, ethanol intake, and abstinence from alcohol in alcoholic individuals. Methods: Ten male current alcoholic individuals were admitted to the study. Baclofen was orally administered for 4 weeks, at a dose of 15 mgiday refracted in three times per day for the first 3 days, with the dose increased to 30 mgiday for the remaining 27 days. Each subject was checked as an outpatient every week for the 4 weeks; at each visit (TO-T4) craving level was evaluated by the Alcohol Craving Scale (ACS), and abstinence from alcohol was assessed based on the individual’s self-evaluation, family member interview, and the main biological markers of alcohol abuse. A self-reported alcohol intake was recorded as the mean number of standard drinks consumed per day. Results: Nine subjects completed the study; of these, two subjects continued to drink alcohol although they substantially reduced their daily drinks in the first week of treatment, whereas seven maintained abstinence throughout the experimental period. Craving was significantly reduced from the first week of the drug administration f$ < 0.01) and remained so throughout the entire treatment period. Participants also reported that obsessional thinking about alcohol disappeared. Values of y-glutamyltranspeptidase, alanine aminotransferase, and mean cellular volume significantly decreased by the end of the study. Tolerability was fair in all participants; headache, vertigo, nausea, constipation, diarrhea, abdominal pain, hypotension, increased sleepiness, and tiredness were present as side effects in the first stage of the treatment. No participants showed craving for the drug. Conclusions: With the limitations of the low number of individuals evaluated and the open design, this preliminary clinical study supports the preclinical evidence on the effect of baclofen in reducing alcohol intake. The anticraving properties of the drug suggest a possible role of baclofen in the treatment of individuals with alcohol problems.

Ability of baclofen in reducing alcohol intake and withdrawal severity: I--Preclinical evidence.

Abstract: Background: The similarities between the pharmacological effects of the γ-aminobutyric acid receptor agonist, baclofen, and the alcohol-substituting agent, γ-hydroxybutyric acid, led us to investigate whether baclofen was capable of reducing (a) ethanol withdrawal syndrome in ethanol-dependent rats and (b) voluntary ethanol intake in ethanol-preferring rats. Methods: In experiment 1, Wistar rats were rendered physically dependent on ethanol by the repeated administration of intoxicating doses of ethanol for 6 consecutive days. Baclofen was acutely administered intraperitoneally at doses of 10, 20, and 40 mg/kg. In experiment 2, baclofen (0, 2.5, 5, and 10 mg/kg, intraperitoneally) was administered once a day for 14 consecutive days to ethanol-preferring sP rats that had continuous access to ethanol (10%, v/v) and water under the two-bottle free choice regimen. Results: In experiment 1, baclofen dose-dependently decreased the intensity of ethanol withdrawal signs; furthermore, 20 mg/kg of baclofen protected from audiogenic seizures in ethanol-withdrawn rats. In experiment 2, baclofen selectively and dose-dependently reduced voluntary ethanol intake; a compensatory increase in water intake left total fluid intake virtually unchanged. Conclusions: These results are in close agreement with those of a preliminary clinical study and suggest that baclofen may constitute a novel therapeutic agent for alcoholism.

Involvement of nicotinic receptors in alcohol self-administration.

Abstract: Background: Alcohol and nicotine, in the form of tobacco, are commonly co-abused. Nicotinic receptors also have been implicated in alcohol action. We designed the present study to examine the possible involvement of nicotinic receptors in alcohol self-administration. Methods and Results: Pretreatment with lower doses (0.1–0.4 mg/kg) of nicotine, administered acutely or chronically, did not affect alcohol consumption, whereas a higher dose (0.8 mg/kg) initially suppressed alcohol consumption but stimulated alcohol consumption on repeated treatment. We observed the same pattern of nicotine effects on alcohol self-administration using an operant procedure. A dose of 0.8 mg/kg of nicotine initially suppressed operant responding for alcohol. Such suppression of alcohol self-administration was more pronounced during the first 20 min of the 60 min operant session. Responding for alcohol in the nicotine treated group, however, was significantly increased above the saline treated group by the 5th day of treatment. Mecamylamine, a noncompetitive nicotinic receptor antagonist, reduced alcohol consumption, whereas dihydro-β-erythroidine (DHβE), a competitive nicotinic receptor antagonist, did not modify alcohol consumption. Conclusions: The stimulation of alcohol intake induced by nicotine treatment and the suppression of alcohol intake induced by mecamylamine provide evidence for the involvement of nicotinic receptors in alcohol consumption and/or self-administration. The failure of DHβE to reduce alcohol consumption, however, suggests that ethanol-nicotine interaction is mediated by other nicotinic receptor subtypes rather than α4β2 receptor subtype, or that mecamylamine acts through a nonnicotinic mechanism.

Adolescents are not adults: developmental considerations in alcohol users.

Abstract: Much of the work in adolescent substance abuse assessment and treatment has been a direct transport from tools and modalities used in adult substance use populations. There was a consensus among symposium participants that developmental issues are important in assessment, evaluation, and treatment of adolescents with substance use disorders. These issues directly impact outcome at all levels. Presentations from the symposium may be helpful for conceptualizing the problems of adolescent substance use as well as formulating strategies for future research. Information from the symposium may be viewed as a springboard for future research and clinical intervention in adolescent substance abuse.

Rearing experiences and stress-induced plasma cortisol as early risk factors for excessive alcohol consumption in nonhuman primates.

Abstract: BACKGROUND: The purpose of this study was to assess the impact of early rearing and stress-induced rise of plasma cortisol collected during infancy as a biological predictors of adult alcohol consumption in nonhuman primates. METHODS: Ninety-seven female and male rhesus macaques (Macaca mulatta) were investigated. They were reared for their first 6 months of life either without mothers or other adults but with constant access to same-aged peers (peer-reared), or as controls with their mothers (mother-reared). When subjects reached 6 months of age, they underwent a series of four sequential weeks of 4-day social separations. Blood was drawn 1 and 2 hr after initiation of the 4-day separation periods, and the plasma was assayed for plasma cortisol concentrations. When the subjects were young adults (approximately 50 months of age), they were tested for voluntary intake of alcohol for 1 hr per day, 4 days a week, during a period of 5 to 7 weeks under normal living conditions. RESULTS: The social separation challenge increased infant plasma cortisol concentrations, with peer-reared subjects exhibiting higher stress-induced cortisol concentrations than mother-reared animals. Subjects that responded to the social separation challenge with high cortisol levels consumed significantly more alcohol per kilogram of body weight as adults than subjects with a low cortisol response to the separation challenge, regardless of rearing condition. In addition, male and peer-reared subjects consumed significantly more alcohol than female and mother-reared subjects, respectively. CONCLUSIONS: These findings suggest that early rearing experiences, such as adult absence, and high plasma cortisol concentrations early in life after a social separation stressor, are useful psychobiological predictors of future high alcohol consumption among nonhuman primates.

High Salivary Acetaldehyde After a Moderate Dose of Alcohol in ALDH2‐Deficient Subjects: Strong Evidence for the Local Carcinogenic Action of Acetaldehyde

Abstract: Background: Due to a point mutation, aldehyde dehydrogenase-2 (ALDH2) isoenzyme is deficient in 30% to 50% of Asians. Among Asian ALDH2-deficient heavy drinkers, the risk for digestive tract cancers is markedly increased (odds ratio 3.4-54.2). The reason for this is unknown but could be due to the local carcinogenic action of acetaldehyde. Methods: Salivary and blood acetaldehyde levels were determined in 20 healthy Asians after a moderate dose of alcohol (0.5 g/kg of body weight). Salivary acetaldehyde production capacity from ethanol in vitro was measured also. ALDH2 genotype of the Asians was determined from isolated leukocyte-deoxyribonucleic acid by polymerase chain reaction/restriction fragment length polymorphism method. Acetaldehyde content of parotid gland saliva was measured in three ALDH2-deficient Asians and three White subjects with normal ALDH2 after the same dose of ethanol. Results: Seven of the Asians were heterozygous for the mutant ALDH2 * 2 allele (flushers). They had two to three times higher salivary acetaldehyde levels than the Asians (n = 13) with normal ALDH2 throughout the follow-up period of 240 min (p <0.001). Only in the flushers did the parotid gland contribute to salivary acetaldehyde production. The in vitro capacity of saliva to produce acetaldehyde from ethanol was equal in both groups. The flushers' blood acetaldehyde levels were only one ninth of the levels in saliva. Conclusions: By using this human knockout model for deficient acetaldehyde removal, we found that in addition to oral microflora, acetaldehyde in saliva may also originate from the oxidation of ethanol in the parotid gland. When combined with earlier epidemiological data, these results offer a strong evidence for the local carcinogenic action of acetaldehyde in humans.

Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: relation to severity of liver disturbance

Abstract: Background: Endotoxin plays an important role in the initiation and aggravation of alcoholic liver disease. In this study, we evaluated plasma endotoxin levels and serum concentrations of cytokines and lipopolysaccharide binding protein (LBP) during the acute and recovery phase of patients with alcoholic hepatitis; we also explored the prognostic factors associated with a fatal outcome. Methods: Fourteen patients, consisting of eight patients with alcoholic hepatitis (AH), five cirrhotics with superimposed AH (LC+AH), and one patient with severe alcoholic hepatitis (SAH), were studied. Among these, two with LC+AH died of hepatic failure. Results: Plasma endotoxin levels in the acute phase were higher in patients with AH (184.4 ± 159.4 pg/ml) and LC+AH (206.9 ± 174.9 pg/ml) than in healthy subjects (10.4 ± 5.5 pg/ml, p < 0.001). In particular, in one patient with SAH and one of two nonsurvivors, plasma cndotoxin levels were markedly high relative to the other cases. In most survivors, plasma endotoxin levels decreased in the recovery phase, whereas they further increased at the terminal stage in one of two nonsurvivors. Serum interleukin (IL)-6 and IL-8 levels in the acute phase were significantly higher in patients with AH and LC+AH as compared with healthy subjects. These levels were especially high in nonsurvivors and in one patient with SAH. IL-10 increased in two nonsurvivors, one patient with SAH, and one with LC+AH. In the recovery phase, these cytokine levels in survivors tended to decrease, but in nonsurvivors, IL-6 remained high, and IL-8 and IL-10 further increased. Tumor necrosis factor-a levels were below the detection limit throughout the course in all patients. Serum lipopolysaccharide binding protein (LBP) generally was elevated in the acute phase and decreased in the recovery phase in all survivors, but in one of the nonsurvivors, LBP was elevated markedly at the terminal stage. In the acute phase, plasma endotoxin levels were correlated positively with white blood cell counts, neutrophil counts, and serum IL-8. IL-8 was correlated positively with neutrophil counts and negatively with serum cholinesterase, hepaplastin test, and serum albumin levels. IL-6 was correlated positively with white blood cell and neutrophil counts, C-reactive protein, and serum total bilirubin and negatively with hepaplastin test and serum total protein levels. Serum LBP was correlated positively with white blood cell and neutrophil counts. Conclusions: Endotoxemia and related elevation of IL-8 may play an important role in the activation and migration of neutrophils in patients with alcoholic hepatitis. Marked elevation of inflammatory cytokines, IL-6 and IL-8, are related to severity and poor prognosis of alcoholic hepatitis. Serum LBP may serve as an index of inflammatory reaction in alcoholics.

Parent ratings of behavior in children with heavy prenatal alcohol exposure and IQ-matched controls.

Abstract: Background: Behavioral disturbances are well documented in children with heavy prenatal alcohol exposure. However, the degree to which these disturbances are related to factors other than alcohol, such as general intellectual functioning or socioeconomic status, is not known. Methods: Using the Child Behavior Checklist, parent-rated behaviors of children with histories of heavy prenatal alcohol exposure were compared with those of a control group matched by age, sex, socioeconomic status, ethnicity, and verbal IQ score. Using this same questionnaire, children with fetal alcohol syndrome were compared with children with heavy prenatal alcohol exposure that did not meet the criteria for fetal alcohol syndrome classification. Results: Data were analyzed by multivariate analyses of covariance. In the comparison of children with and without a history of prenatal alcohol exposure, significant differences were found on the competence, problem, and summary scales (all p 0.10). Conclusions: These results suggest that prenatal alcohol exposure results in the significant and profound impairment of parent-rated behaviors and that these deficits are not explained entirely by the presence or absence of facial dysmorphology, general intellectual functioning, or demographic factors.

Subjective and objective responses to ethanol in moderate/heavy and light social drinkers.

Abstract: Background: Individuals who drink heavily are at an increased risk for adverse consequences of drinking and progression of their drinking habits to abuse or dependence. Therefore, it is important to delineate factors associated with their heavy drinking. Methods: We examined individual differences in subjective and objective responses to ethanol associated with level of consumption by reanalyzing data from the nine heaviest and nine lightest social drinkers from each of two independently collected subject samples: Holdstock and de Wit (1998) and King et al. (1997). The light drinkers in both samples consumed five or less alcoholic drinks per week, whereas the moderate/heavy drinkers consumed eight or more drinks per week with frequent binge episodes. Acute subjective and objective responses to ethanol (0.6 or 0.8 g/kg) or placebo were compared in the two groups at baseline and during rising and falling blood alcohol concentrations. Results: Moderate/heavy drinkers reported greater stimulant-like and fewer sedative-like and aversive subjective effects after ethanol than did lighter drinkers. These differences occurred in the absence of any group differences in breath alcohol levels, performance effects, or neuroendocrine changes or in overall reports of feeling any drug effects. Conclusions: These data indicate that habitual moderate/heavy ethanol use was associated with greater stimulant-like effects after an acute dose of alcohol. This finding is consistent with the idea (Newlin and Thomson, 1990, 1999) that individuals who experience greater stimulant-like effects during the ascending limb and lesser sedative-like effects on the descending limb of the blood alcohol concentration curve may be at greater risk for developing ethanol use disorders. Although we cannot determine the causality of this association, sensitivity to the stimulant effects of ethanol may play an important role in the continuation of heavy ethanol use and the increased risk of negative consequences from this use.

Alcohol Consumption, Alcohol Dependence, and All-Cause Mortality

Abstract: Background: This study examined the effects of alcohol consumption and DSM-IV alcohol dependence on the risk of mortality. Methods: Data from the 1988 National Health Interview Survey Alcohol Supplement were matched to the National Death Index for the years 1988 to 1995 (baseline n= 37,682 U.S. adults age ≥25 linked to 3,586 deaths). All mortality analyses were based on proportional hazards models that adjusted for age, sex, race/ethnicity, marital status, education, income, labor force status, body mass index, smoking status, and poor health indicators at baseline. Results: When dependence was not considered and all past-year abstainers were used as the reference group, both light and moderate drinkers exhibited a reduced risk of mortality, with hazards ratios of 0.76 (0.68–0.84) and 0.84 (0.74–0.96). Heavy drinkers had about the same risk of dying as did past-year abstainers, and very heavy drinkers had an increased risk that was not significant (OR = 1.17, CI = 0.93–1.47). When lifetime abstainers were used as the reference category, the protective effect of moderate drinking fell short of significance, and there were nearly significant increased risks among former drinkers and very heavy drinkers. When dependence was considered, light and moderate drinkers without dependence had a reduced mortality risk regardless of reference group, and there was no significant effect among heavy or very heavy drinkers without dependence. Among dependent drinkers, there was no protective effect of light or moderate drinking, and very heavy drinkers had a significantly increased risk (OR = 1.56 relative to past-year abstainers and 1.65 relative to lifetime abstainers). Conclusions: Because alcohol dependence nullifies the protective effect of light and moderate drinking, it is important to understand its role as an independent risk factor for mortality. Differences between dependent and nondependent drinkers who drank comparable amounts suggest that this risk may result from longer and heavier drinking histories before baseline, more severe health problems at baseline, more heavy episodic drinking, and, possibly, differences in beverage preference.

Amelioration of Ethanol‐Induced Neurotoxicity in the Neonatal Rat Central Nervous System by Antioxidant Therapy

Abstract: Background: The cerebellum of the neonatal rat is highly susceptible to ethanol, with profound loss of Purkinje cells resulting from even brief exposure during the first postnatal week. Developmental ethanol exposure previously has been shown to induce free radicals/oxidative stress processes and/or down-regulate protective antioxidants. In an earlier study, we found antioxidants protected against ethanol neurotoxicity in a tissue culture environment. The present study was designed to determine whether similar protection could be manifested in the intact animal. Methods: Neonatal rats were administered a liquid diet via intragastric intubation on postnatal days 4 and 5 (P4-P5), the peak period of ethanol sensitivity in the developing cerebellum. The diet consisted of milk formula with 12% ethanol, the isocaloric substitution of maltose-dextrin for ethanol, or ethanol plus the antioxidant vitamin E. Unbiased three-dimensional counting was utilized to analyze Purkinje cell numbers and density within defined volumes from these animals on P5. Results: These determinations revealed a substantial loss of Purkinje cells in the ethanol-treated animals compared to controls (approximately 30-44%), but this loss was prevented by the inclusion of vitamin E (60IU/100 ml) in the diet. A lower concentration of the antioxidant (30IU/100 ml) was not effective in this regard, however. Conclusions: These results suggest that ethanol-related cerebellar damage during this early postnatal period may be related to oxidative stress processes or the insufficiency of protective antioxidants. Thus, antioxidant treatment may represent a possible therapy for preventing or ameliorating the central nervous system (CNS) damage seen in the fetal alcohol syndrome.

Treatment of problem alcohol use in women of childbearing age: results of a brief intervention trial.

Abstract: Background: Studies suggest that 14% of women age 18 to 40 drink alcohol above recommended limits. Of special concern is the increasing use of alcohol by women during pregnancy. This article reports 48 month follow-up data from a subanalysis of a trial for early alcohol treatment (Project TrEAT) focused on women of childbearing age. Methods: Project TrEAT was conducted in the offices of 64 primary care, community-based physicians from 10 Wisconsin counties. Of 5979 female patients ages 18 to 40 who were screened for problem drinking, 205 were randomized into an experimental group (n = 103) or control group (n = 102). The intervention consisted of two 15 min, physician-delivered counseling visits that included advice, education, and contracting by using a scripted workbook. A total of 174 subjects (85%) completed the 48 month follow-up procedures. Results: No significant differences were found between the experimental and control groups at baseline for alcohol use, age, socioeconomic status, smoking, depression or anxiety, conduct disorder, lifetime drug use, or health care utilization. The trial found a significant treatment effect in reducing both 7 day alcohol use (p = 0.0039) and binge drinking episodes (j~ = 0.0021) over the 48 month follow-up period. Women in the experimental group who became pregnant during the follow-up period had the most dramatic decreases in alcohol use. A logistic regression model based on a 20% or greater reduction in drinking found an odds ratio of 1.93 (confidence interval 1.07-3.46) in the sample exposed to physician intervention. Age, smoking, depression, conduct disorder, antisocial personality disorder, and illicit drug use did not reduce drinking significantly. No significant differences were found in health care utilization and health status between groups. Conclusions: This trial provides the first direct evidence that brief intervention is associated with sustained reductions in alcohol consumption by women of childbearing age. The results have enormous implications for the US. health care system.

The value of CAGE, CUGE, and AUDIT in screening for alcohol abuse and dependence among college freshmen.

Abstract: Background: This study attempted to (1) determine the prevalence of alcohol problems in college freshmen, (2) assess the performance of both the CAGE and the Alcohol Use Disorders Identification Test (AUDIT) questionnaires in this population, and (3) assess the possibility of improving the CAGE and/or AUDIT. Methods: A sample of 3564 consecutive college freshmen, with a mean age of 18 years, at the Catholic University of Leuven, (Belgium) completed, during a cross-sectional study, a questionnaire assessing drinking behavior and identifying students at risk as defined by DSM-IV criteria. The questionnaire also included the CAGE questionnaire and the AUDIT. Calculations of sensitivity, specificity, negative predictive value, positive predictive value, likelihood ratios, and receiver operating characteristic curves for different scores of the CAGE and the AUDIT were performed, using DSM-IV criteria as the reference standard. Results: The area under the receiver operating characteristic curve of the CAGE and the AUDIT was 0.76 and 0.85, respectively. The cutoff score of 1 for the CAGE was associated with a sensitivity of 42%, a specificity of 87%, a positive predictive value of 36%, and a negative predictive value of 90%. A score of 6 or more for the AUDIT gave a sensitivity of 80%, a specificity of 78%, a positive predictive value of 37%, and a negative predictive value of 77%. These results were related with a prevalence of 14.1% of alcohol problems. Replacing one question of the CAGE by “often driving under the influence'’resulted in the CUGE (acronym for “cut down, under influence, guilty feelings, and eye opener”), with an area under the curve of 0.96, a positive likelihood ratio of 8.7, and a negative likelihood ratio of 0.04. Conclusions: Prevalence of alcohol problems in college students is confirmed to be high. When screening for alcohol problems in a college freshmen population, one question seems extremely important. The newly constructed CUGE questionnaire may improve screening efforts in students, compared with existing questionnaires.