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Alcoholism is one of the most challenging current health problems in the Western countries with far-reaching medical, social, and economic consequences. There are a series of factors that interact in predisposing or protecting an individual against alcoholism and alcohol-related disorders. This article surveys the state of our knowledge concerning the biochemical and genetic variations in alcohol metabolism and their implications in alcohol sensitivity, alcohol drinking habits, and alcoholism in different racial/ethnic groups. The major pathway for the degradation of ethanol is its oxidation to hydrogen and acetaldehyde--to which many of the toxic effects of ethanol can be attributed. Variations in alcohol and acetaldehyde metabolism via genetically determined polymorphisms in alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) seem to play an important role in individual and racial differences in acute and chronic reactions to alcohol, alcohol drinking habits, as well as vulnerability to organ damage after chronic alcohol abuse. Alcohol sensitivity and associated discomfort symptoms accompanying alcohol ingestion may be determinental for the significantly low incidence of alcoholism among the Japanese, Chinese and other Orientals of Mongoloid origin. An abnormal ALDH isozyme has been found to be widely prevalent among individuals of the Mongoloid race and is mainly responsible for the acute sensitivity to alcohol commonly observed in this race. Persons sensitive to alcohol by virtue of their genetically controlled ALDH isozyme deficiency may be discouraged from drinking large amounts of alcohol in their daily life due to the initial adverse reaction experienced after drinking alcohol. Indeed, a significantly low incidence of the mitochondrial ALDH isozyme deficiency has been observed in alcoholics as compared to psychiatric patients, drug dependents and healthy controls in Japan. How far any variation in ADH and/or ALDH activity among individuals of Caucasian origin will have similar effects has yet to be studied.
CONTEXT: The ALDH2*2 allele has been shown to be a protective factor against alcoholism in a normal population owing in part to the elevated blood level of acetaldehyde and its accompanying physiological discomforts after drinking alcohol. Despite the well-established link between the ALDH2*2 allele and the physiological discomforts after drinking, very little is known regarding the psychological expectancies of drinking among persons with alcoholism with different ALDH genotypes. OBJECTIVES: To determine whether there are differences in craving, alcohol consumption, and alcohol outcome expectancies between persons with alcoholism who have the ALDH2*1/*2 genotype and persons with alcoholism who have the ALDH2*1/*1 genotype. DESIGN: Cross-sectional survey. SETTING: Six outpatient alcohol treatment facilities in Taiwan. PARTICIPANTS: Ninety-eight persons with alcoholism who met the DSM-IV criteria for current alcohol dependence. MAIN OUTCOME MEASURES: Alcohol Craving Scale, Form 90, and Alcohol Expectancies Scale scores. RESULTS: Overall, the ALDH2*1/*2 group had lower negative alcohol outcome expectancies (F(4,93) = 2.43, P < or = .05, eta(p)2 = 0.10). Specifically, they had fewer expected negative outcomes in the social or interpersonal domain (P < .05) and the emotional and physical domain (P < or = .005) than did the ALDH2*1/*1 group. Moreover, the ALDH2*1/*2 group had higher positive alcohol outcome expectancies (F(7,90) = 2.36, P < .05, eta(p)2 = 0.16), and they had more expected positive outcomes in the relaxation and tension reduction domain (P < .05). The 2 groups did not differ in alcohol craving (P = .61) or consumption (P = .11). CONCLUSIONS: Although the ALDH2*2 allele has been associated with negative physiological responses in normal samples in past research, the psychological expectancies of drinking are more positive and less negative for persons with alcoholism who have the ALDH2*1/*2 genotype. A role of acetaldehyde is implied in these effects, which seem to override the usual discomfort effects associated with protection against alcohol drinking. Future studies are needed to assess alcohol outcome expectancies at different phases of alcohol dependence and to evaluate the concurrent relationships of blood levels of acetaldehyde with physiological and psychological outcomes among persons with alcoholism who have different ALDH genotypes.
An association between saccharin consumption and alcohol intake has been observed in rodent lines genetically developed for alcohol preference or alcohol avoidance. It has also been proposed that a sweetened alcohol solution can condition rats to consume high amounts of alcohol. This work had two aims. First, to study the relationship between saccharin and alcohol intake in both high-alcohol-drinking UChB rats and low-alcohol-drinking UChA rats and, second, to determine whether a long-term exposure to a sweetened alcohol solution can increase their voluntary alcohol consumption. For the first purpose, UChB and UChA rats were tested under a free-choice paradigm between two graduated bottles, one containing a saccharin solution (0.1, 0.2, or 0.4% [wt/vol]) and the other water. For the second purpose, UChB and UChA rats that were under free choice between 10% alcohol and water, were offered a 10% alcohol solution containing 0.2% saccharin, instead of 10% alcohol for 1 month and were then returned to free choice between 10% alcohol and water. The first experiment showed that both lines have a high preference for saccharin at any concentration, but UChB rats drank twice as much saccharin solution as UChA rats and consequently they increased significantly their total daily fluid intake. This fact has been suggested to be an animal analogue of the clinical phenomenon known as "loss of control." In the second experiment a long-term exposure to a 10% alcohol solution containing 0.2% saccharin induced a significant increase in alcohol consumption in UChB rats once saccharin was faded out, whereas the alcohol consumption in UChA rats returned to the previous low value. This result indicates that UChA rats have a genetic predisposition to avoid alcohol. In conclusion, the results reported here for UChB and UChA rats show an association between saccharin and alcohol preference, and suggest that their different genotypes are probably involved in alcohol aversion.
RATIONALE: Alcohol-induced heart rate (HR) stimulation during the rising limb of the blood alcohol curve reliably discriminates between individuals at differential risk for alcoholism, and appears to be a potential psychophysiological index of psychomotor stimulation from alcohol. OBJECTIVES: Three studies are presented which explore the reliability and convergent and discriminant validity of this alcohol response index. METHODS: Young men with and without a multigenerational family history of alcoholism were administered a 1.0 ml/kg dose of 95% USP alcohol. Resting baseline cardiac and subjective measures were assessed before and after alcohol consumption. RESULTS: Study 1 demonstrated that alcohol-induced HR stimulation was significantly and positively related to alcohol-induced changes in mood. Study 2 demonstrated that alcohol-induced HR stimulation was reliable across two alcohol administration sessions (r=0.33-0.66, P<0.01). Study 3 explored the relationship between the proposed index and measures of sensitivity to alcohol previously linked to genetic predisposition to alcoholism. Multiple regression analysis indicated that alcohol-induced HR increase and reduced subjective intoxication (measured using the Subjective High Assessment Scale) were both positively associated with alcohol-induced changes in mood states that have previously been shown to be sensitive to the effects of stimulant drugs and the reinforcing effects of alcohol. CONCLUSIONS: Sensitivity to alcohol-induced heart-rate stimulation during the ascending limb of the blood alcohol curve may be a useful and informative marker for understanding susceptibility to alcoholism.
PURPOSE: Alcohol is the most common and frequently used drug and has the potential to cause multiple deleterious effects throughout the lifespan. Because early age at initiation of alcohol use increases this potential and programs and laws are in place to attempt to delay the onset of alcohol use, we studied the relationship between multiple adverse childhood experiences (ACEs) and both the likelihood of ever drinking and the age at initiating alcohol use. METHODS: This was a retrospective cohort study of 8417 adult health maintenance organization (HMO) members in California who completed a survey about ACEs, which included childhood abuse and neglect, growing up with various forms of household dysfunction and alcohol use in adolescence and adulthood. The main outcomes measured were ever drinking and age at initiating alcohol use among ever-drinkers for four age categories: < or = 14 years (early adolescence), 15 to 17 years (mid adolescence), and 18 to 20 years (late adolescence); age > or = 21 years was the referent. The relationship between the total number of adverse childhood experiences (ACE score) and early initiation of alcohol use (< or =14 years) among four birth cohorts dating back to 1900 was also examined. RESULTS: Eighty-nine percent of the cohort reported ever drinking; all individual ACEs except physical neglect increased the risk of ever using alcohol (p < .05). Among ever drinkers, initiating alcohol use by age 14 years was increased two- to threefold by individual ACEs (p < .05). ACEs also accounted for a 20% to 70% increased likelihood of alcohol use initiated during mid adolescence (15-17 years). The total number of ACEs (ACE score) had a very strong graded relationship to initiating alcohol use during early adolescence and a robust but somewhat less strong relationship to initiation during mid adolescence. For each of the four birth cohorts, the ACE score had a strong, graded relationship to initiating alcohol use by age 14 years (p < .05). CONCLUSIONS: Adverse childhood experiences are strongly related to ever drinking alcohol and to alcohol initiation in early and mid adolescence, and the ACE score had a graded or "dose-response" relationship to these alcohol use behaviors. The persistent graded relationship between the ACE score and initiation of alcohol use by age 14 for four successive birth cohorts dating back to 1900 suggests that the stressful effects of ACEs transcend secular changes, including the increased availability of alcohol, alcohol advertising, and the recent campaigns and health education programs to prevent alcohol use. These findings strongly suggest that efforts to delay the age of onset of drinking must recognize the contribution of multiple traumatic and stressful events to alcohol-seeking behavior among children and adolescents.
OBJECTIVE: The present study was undertaken to assess the rate and severity of alcohol craving symptoms among registered alcohol-dependent patients at a Veterans Affairs outpatient clinic. We also examined the relationship between alcohol craving and the clinical characteristics of alcohol-dependent patients. METHOD: Participants included 101 alcohol-dependent veterans enrolled in an outpatient addiction clinic. Alcohol craving was measured by the Penn Alcohol Craving Scale. Alcoholism severity and clinical characteristics were assessed with the Addiction Severity Index, Timeline Followback method, and other instruments. Three alcohol-craving groups (low, moderate, and high) were identified and compared using their demographic and clinical characteristics. Multiple regression analysis was performed to evaluate the relationship between the potential predictors and alcohol craving. RESULTS: The rate of alcohol craving was as follows: low craving (46%), moderate craving (29%), and high craving (25%). When these three craving groups were compared using univariate analyses, patients with higher alcohol craving had significantly higher alcohol composite scores (last 30 days) and severe alcohol dependence (last 1 year). In multiple regression analysis, the model explained 50% of the variance in alcohol craving, with alcoholism severity (42%), withdrawal symptoms (5%), and depression (3%) as significant predictors. CONCLUSIONS: Patients in an outpatient treatment setting had a wide range of alcohol cravings. Level of alcohol craving was directly associated with several increased indices of alcohol- and non-alcohol-related morbidity.
Excessive alcohol ingestion disturbs the metabolism of most nutrients. Although alcohol can lead to severe hypoglycemia, alcoholics are usually glucose intolerant, probably due to a inhibition of glucose-stimulated insulin secretion. Ethanol intake also leads to negative nitrogen balance and an increased protein turnover. Alcohol also alters lipid metabolism, causing a profound inhibition of lipolysis. Looking for an association between alcohol intake, nutrition, and alcoholic liver disease, we have observed a higher prevalence of subclinical histologic liver damage among obese alcoholics. Multivariate analysis in a large group of alcoholics has shown that obesity is an independent predictor of alcoholic liver disease. Other authors have reported that alcoholics with a history of obesity have a two to three times higher risk of having alcoholic liver disease than non-obese alcoholics. The possible explanation for this association is that the microsomal system, which plays an important pathogenic role in alcoholic liver disease, is induced in non-alcoholic obese subjects and alcoholics. Also, peripheral blood monocyte cells of obese alcoholics produce higher levels of interleukin-1, a cytokine that can contribute to liver damage. The ingestion of polyunsaturated fatty acids can also increase the damaging effects of alcohol on the liver, as has been demonstrated in rats subjected to continuous intragastric infusion of alcohol. Observations in human alcoholics have shown that liver damage is associated with a higher ratio of C:18:1/C:18:0 and a lower ratio of C:22:4/C:18:2 in liver lipids, consistent with an induction of delta 9 desaturase and an increased peroxidation of C:22:4.
Observing responses produce contact with stimuli that are to be discriminated and have been considered an animal model of attending. In the observing-response procedure, alternating periods of drug availability versus extinction for one response are not signaled, but a second response (i.e. the observing response) produces stimuli signaling whether drug is available or not. This experiment examined the effects of the concentration of self-administered alcohol and increases in observing-response requirement on rats' observing alcohol stimuli. In addition, the effects of alcohol concentration on the persistence of observing were examined when alcohol was no longer available. Results showed that observing tracked bitonic changes in the number of alcohol deliveries rather than monotonic increases in total alcohol consumption resulting from increases in alcohol concentration. Increasing the observing-response requirement decreased the number of stimulus presentations earned. The resultant decreases in time spent in the presence of the alcohol stimulus were associated with decreases in alcohol consumption. During extinction of alcohol responding, observing was more persistent when it produced a stimulus previously associated with a higher alcohol concentration. Finally, responding for alcohol was more resistant to extinction in the presence of an observing-response-produced alcohol stimulus than in its absence, but did not depend on alcohol concentration. These results suggest that increases in the difficulty of obtaining access to alcohol cues can decrease alcohol consumption by reducing contact with those cues. In addition, if observing behavior in the present procedure is analogous to attending to alcohol cues, the results suggest that attending to alcohol cues is more persistent with cues previously associated with higher doses, and that the persistence of attending to alcohol cues and their impact on drinking may be dissociable.
This study was conducted to determine the temporal and regional vulnerability of the brain as a function of exposure to alcohol during brain development. Our goal was to manipulate the timing of alcohol exposure and assess the relative risk of cell loss in two different brain regions. Groups of timed pregnant Sprague-Dawley rats received binge-like alcohol exposure during either the first 10 days (first-trimester equivalent) or second 10 days of gestation (second-trimester equivalent), or the combination of first- and second-trimester equivalents for prenatal treatments. Offspring from some of the animals exposed to alcohol during the combined first- and second-trimester equivalent were reared artificially from postnatal days (P) 4 through 9 (part of the third-trimester equivalent) and also received binge-like alcohol during this period, producing animals that were exposed to alcohol during all three trimesters equivalent. Offspring from untreated dams were also reared artificially and received alcohol from only P4-9, thus creating animals that were exposed to alcohol only during part of the third-trimester equivalent. All pups were perfused on P10. Appropriate controls (nutritional and normally reared) were matched to every alcohol treatment combination. Peak blood alcohol concentrations were not different among the treatment groups for a given sampling time. Total cell numbers in the cerebellum (Purkinje and granule cells) and the olfactory bulb (mitral and granule cells) were estimated by the unbiased stereological technique, the optical disector. In terms of temporal vulnerability, alcohol exposure during the equivalent of all three trimesters resulted in a greater reduction in cerebellar Purkinje cell numbers compared with exposure to alcohol during the third-trimester equivalent, whereas both groups had a significant reduction in cell number compared with all other timing groups. Cerebellar granule cell number was reduced after alcohol exposure during all three trimesters equivalent, compared with all other timing groups. Alcohol exposure during the third-trimester equivalent resulted in a decrement in the number of olfactory bulb mitral cell numbers compared with all other groups, but there were no differences among the timing groups in numbers of olfactory bulb granule cells. When the cell loss in the two regions was compared within each alcohol treatment group to determine the relative regional vulnerability, the primary salient finding was that cerebellar Purkinje cells were more vulnerable to alcohol-induced loss subsequent to exposure during all three trimesters equivalent. No other regional differences were detected. These results extend earlier findings by showing that alcohol exposure during different periods of brain development results in regional differences in cell loss as a function of the timing of alcohol exposure during brain development and illustrate the variability of alcohol-induced neuronal loss.
OBJECTIVE: This study examines whether the age of initiation of alcohol use mediates the effects of other variables that predict alcohol misuse among adolescents and also whether the age of initiation of alcohol use accounts for known gender differences in the severity of alcohol misuse. METHOD: Data were taken from an ethnically diverse sample of 808 (412 male) students who were recruited in grade 5 at age 10-11 and followed prospectively on an annual basis for the next 7 years to age 17-18. State-of-the-art missing data methodology was used to address nonresponse due to noninitiation of alcohol use. Structural equation modeling was used to examine hypotheses for the prediction of alcohol misuse. RESULTS: A younger age of alcohol initiation was strongly related to a higher level of alcohol misuse at age 17-18 and fully mediated the effects of parent drinking, proactive parenting, school bonding, peer alcohol initiation and ethnicity, all measured at age 10-11, and perceived harmfulness of alcohol use, measured at age 10-11 and age 11-12. However, age of alcohol initiation did not fully account for gender differences in the level of alcohol misuse at age 17-18. To further examine the role of gender, interactions between gender and school bonding, and gender and friend's alcohol initiation, were evaluated. However, neither of the interaction terms had direct effects on either age of initiation or level of alcohol-related problems. CONCLUSIONS: Most measured risk factors for alcohol misuse were mediated through age of alcohol initiation. Only gender differences in alcohol misuse at age 17-18 were not mediated by age of alcohol initiation. Variables associated with these differences require further study. The results of this study indicate the importance of prevention strategies to delay the age of initiation of alcohol use.
AIMS: A low level of response (LR) to alcohol is a characteristic of sons of alcoholics and predicts an elevated future alcoholism risk. A 12-question Self-Rating of the Effects (SRE) of alcohol form has been shown to correlate cross-sectionally with a designation of a low LR determined by alcohol challenges. DESIGN: This study evaluates the potential usefulness of the SRE as a retrospective measure of both the response to alcohol and of subsequent alcoholism in two samples. SETTING: All subjects were studied in the United States, most in California. PARTICIPANTS: First, 94 sons of alcoholics and controls completed the SRE 15 years after an alcohol challenge, and SRE values were compared to their prior LR results and their alcoholic outcomes. Secondly, the relationship between SRE results and alcoholic status was determined in 551 men and women alcoholics, their relatives, and controls. MEASUREMENTS: Subjects were evaluated with face-to-face interviews. FINDINGS: Despite the interval of 15 years, the correlation between the SRE and the subjective high feelings on the alcohol challenge was between -0.3 and -0.4. For those 94 subjects the full SRE correlated with a diagnosis of alcohol dependence at 0.5, a figure that remained at 0.3 even when only the estimates related to the earliest drinking experiences were considered. For the 551 men and women, the correlation between the SRE and alcohol dependence diagnoses was 0.6, including 0.3 for the estimates of the first five times of drinking. All major findings in both samples remained robust when the recent drinking history or the number of items endorsed was considered, or when the most severe alcohol problem, passing out, was deleted from the analysis. CONCLUSIONS: When alcohol challenges are not possible, these retrospective reports indicate that the SRE is a potentially useful surrogate for determining a subgroup of people who might carry a low level of response to alcohol and a subsequent elevated risk for alcoholism.
1. Chronic alcohol exposure modifies endocannabinoid levels in different brain regions, while pharmacological targeting of the endocannabinoid system has been reported to influence ethanol intake in laboratory animals. 2. The present study was aimed at evaluating the pattern of changes of endocannabinoids and their receptors, with emphasis on reward-related brain areas, in Wistar rats subjected to consecutive phases of alcoholization, alcohol deprivation (abstinence), and voluntary consumption of alcohol (relapse). 3. We observed that, in the limbic forebrain, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) contents increased after 7 days of alcoholization, then to dramatically decrease after 48 h of alcohol deprivation and, in the case of 2-AG, to further decrease when rats were allowed to relapse to alcohol consumption. By contrast, in the midbrain, there was a marked reduction in AEA, but not 2-AG, content, after alcoholization. This decrease was not affected during alcohol abstinence, but both AEA and 2-AG contents were then significantly reduced when rats were allowed to relapse to alcohol consumption. 4. Based on these data, we examined whether pharmacological activation/blockade of endocannabinoid transmission might influence ethanol intake in rats allowed to relapse to alcohol consumption after subsequent periods of alcoholization and alcohol deprivation. 5. Treatment with either Delta(9)-tetrahydrocannabinol or CP55,940, two cannabinoid agonists, reduced both total liquid and ethanol intake but did not affect ethanol preference. Treatment with SR141716, a selective cannabinoid CB(1) receptor antagonist, also produced a significant reduction in both total liquid and ethanol intake without affecting ethanol preference. Accordingly, none of these effects on ethanol intake were accompanied by changes in dopamine and GABA in limbic structures. 6. In summary, the levels of endocannabinoids underwent significant changes in reward-related areas during alcoholization, alcohol deprivation, and relapse, showing the lowest values in this latter phase. Treatment with cannabinoid agonists or a selective CB(1) receptor antagonist resulted in a reduction of ethanol intake by rats allowed to relapse to alcohol consumption after periods of alcoholization and alcohol deprivation, but these effects did not appear to be due to changes in neurobiological substrates currently involved in alcohol reinforcement/relapse.
BACKGROUND: Heart rate (HR) acceleration during the ascending limb of the blood alcohol curve has proven to be a reliable measure of the sensitivity to the activating effects of alcohol. In this study, we investigated the correlation between an ethanol-induced cardiac change and the strength of implicit alcohol-related arousal and approach associations and attentional bias for alcohol-related stimuli in heavy drinkers. These 3 types of implicit alcohol-related cognitions have been proposed to reflect the strength of incentive sensitization that is experienced after repeated alcohol use. METHODS: Forty-eight heavy drinking men performed a modified version of the Implicit Association Test (IAT) to measure their implicit alcohol arousal and approach-avoidance associations. A modified version of the emotional Stroop was used to measure attentional bias for alcohol-related stimuli (blocked and unblocked). Next, a high dose of alcohol (1.0 mL/kg body weight 95% USP alcohol) was administered in a short period of time. Resting baseline HR, blood alcohol concentrations, mood, and craving for alcohol were assessed before alcohol administration and for 2 hours post-alcohol consumption. RESULTS: Contrary to our hypothesis, a negative association was found between implicit arousal associations and alcohol-induced HR change. This indicates that strong arousal associations were correlated with a decrease in alcohol-induced HR. Approach associations and attentional bias were not correlated with alcohol-induced HR change, but both were correlated positively with each other. CONCLUSIONS: Alcohol-arousal associations and other implicit cognitions (attentional bias, approach associations) are not positively related to individual differences in the sensitivity to alcohol's activating effects, at least not in the present sample consisting primarily of family history-negative heavy drinkers.
OBJECTIVE: This panel study examined the relations between alcohol-specific socialization by parents (monitoring of alcohol use by children, allowing alcohol use by children at home, communicating against alcohol use and setting rules against alcohol use), general dimensions of parenting behavior (responsiveness and demandingness) and alcohol use by children. METHOD: A sample of 488 fifth-grade children reported their perceptions of alcohol-specific socialization by parents, parental responsiveness and parental demandingness. These variables were used to predict alcohol use when children in the panel were in seventh grade. RESULTS: Nineteen percent of seventh-grade children reported alcohol use in the past 30 days. Logistic regression analyses indicated that, after accounting for children's age, sex, single parent status, prior use of alcohol and exposure to parental modeling of alcohol use, the odds of alcohol use were significantly greater among children who perceived no parental monitoring of alcohol use, who had been allowed by parents to have a drink with alcohol at home and who perceived relatively low levels of parental demandingness. Rules against alcohol use, parental communication against alcohol use and parental responsiveness were unrelated to the study outcome. CONCLUSIONS: Parental monitoring of alcohol use by children, family norms regarding alcohol use by children at home and parental ability to set and enforce behavioral rules merit consideration as factors that should be modified by prevention programs. There is a need, however, for additional research that further examines the relations between exposure to such parenting behaviors during childhood and alcohol use during adolescence.