Ethanol ingestion: differences in blood acetaldehyde concentrations in relatives of alcoholics and controls.

Blood acetaldehyde concentrations were significantly elevated after a moderate ethanol dose in 20 healthy young men with alcoholic parents or siblings compared to matched controls with no familial alcoholism.

Genetic factors influencing alcohol dependence.

Plentiful data from both animal and human studies support the importance of genetic influences in substance abuse and dependence (Bierut et al., 1998; Tsuang et al., 1998; Kendler et al., 2003). This review summarizes the evidence supporting such genetic influences, places them into perspective regarding animal and human studies, discusses the importance of both genes and environment, and highlights some specific genes of interest regarding the vulnerabilities for problems associated with alcohol use disorders. A long history of repetitive heavy use of alcohol exists across generations as well as the high prevalence of alcohol-related problems in Western societies. Moreover, the information offered here addresses the importance of more general issues regarding genetics and gene expression related to alcohol abuse and dependence.

Subjective responses to alcohol in sons of alcoholics and control subjects.

We matched 23 nonalcoholic male drinkers who were aged 21 to 25 years and had alcoholic close relatives (FHP) with 23 control subjects with negative family histories (FHN) for demographic characteristics and drinking and smoking histories. The subjective feelings of intoxication for the 46 men were studied on three occasions using placebo, 0.75 mL/kg of ethanol, and 1.1 mL/kg of ethanol. The FHP subjects (at elevated risk for the development of alcoholism) reported less intense feelings of subjective intoxication after drinking, especially during the two hours following the peak blood alcohol concentration (BAC). Group differences were most marked with the 0.75-mL/kg dose. The two groups did not differ significantly on their BACs nor on the expectation of how they would feel under the influence of alcohol.

Ethanol-induced changes in body sway in men at high alcoholism risk.

This study measures the amount of body sway or static ataxia in 34 drinking but nonalcoholic men 21 to 25 years of age who have an alcoholic first-degree relative (the family-history-positive, or FHP, group). Results are compared with 34 control subjects matched pairwise on demographic characteristics and drinking histories, but who have no known alcoholic close relatives (the family-history-negative, or FHN, group). Each man was tested on three occasions where he drank either placebo, or 0.75 mL/kg or 1.1 mL/kg of ethanol; the subjects were repeatedly tested during the subsequent four hours. At the baseline of each of the three test sessions, the level of body sway for the two family-history groups was virtually identical. However, following the 0.75-mL/kg dose, the increase in body sway was significantly less for the FHP than for FHN group, with similar but less dramatic group differences noted following the ingestion of 1.1 mL/kg of ethanol. These results are consistent with the significantly less intense subjective feelings of intoxication after drinking for the FHP men, and also parallel findings of less intense ethanol-related changes in biologic and cognitive test scores. A decreased intensity of reaction to ethanol should be explored further as a possible genetic trait marker of a predisposition toward alcoholism.

The clinical implications of primary diagnostic groups among alcoholics.

Interviews with patients and two resource persons were used to determine primary psychiatric diagnoses in 577 consecutive men entering an alcohol treatment program (ATP) at a veterans hospital. Twelve months later, about 95% of the sample were successfully followed up with a patient and resource person interview to establish the clinical course over the year for the four most populous diagnostic subgroups. At intake into the treatment program, the 432 group 1 primary alcoholic men were older, had a later age at onset of alcoholism, demonstrated a lower intensity of drinking, had fewer antisocial problems, and used fewer categories of drugs than the 60 men in group 2 with primary drug abuse and the 40 men in group 3 with primary antisocial personality disorder. During the follow-up, men in groups 2 and 3 had a greater likelihood of drug use, more police and social problems, and demonstrated higher (more adverse) outcomes on a clinical outcome scale. The nine group 4 men with primary affective disorder at intake demonstrated an increased risk for past suicide attempts and psychiatric care and had a higher rate of affective disorder in first-degree family members. These findings underscore the importance of distinguishing between symptoms (eg, sadness or antisocial problems) and diagnoses and the need to establish primary and secondary labels in substance abusers.

A simultaneous evaluation of multiple markers of ethanol/placebo challenges in sons of alcoholics and controls.

This study evaluates multiple aspects of the reaction to two doses of ethanol (0.75 and 1.1 mL/kg) in 30 sons of alcoholic fathers and 30 matched controls with no known alcoholic relatives. Based on results of prior research, the evaluations included the postethanol changes in subjective feelings, levels of body sway or static ataxia, and plasma levels of prolactin and cortisol. A stepwise discriminant function analysis on the sample of 60 men revealed that four items (maximum terrible subjective feelings after high dose, cortisol values at two time points after high dose, and prolactin results after low dose) combined to correctly identify 83% of the controls and 70% of the sons of alcoholics. This included approximately 40% of each group whose discriminant scores were +1 or -1 and who were considered to be solidly classified. These results were relatively robust on a jackknife validation procedure. Results of a search for independent factors in the cluster of test scores after ethanol using a principal components analysis were consistent with the discriminant analysis, indicating the possibility of three overlapping domains of the ethanol response, including subjective feelings after the high-dose ethanol challenge (explaining 46% of the variance), hormonal changes after high-dose ethanol along with body sway items (14% of variance), and prolactin changes after low-dose ethanol (9% of variance). There were few background differences between men who had been properly and improperly classified.

An 8-year follow-up of 450 sons of alcoholic and control subjects.

BACKGROUND: Between 1978 and 1988, 453 sons (age range, 18-29 years) of alcoholic and control subject were evaluated for their level of reaction (LR) to alcohol. This article presents the results of the 8.2-year follow-up of 450 of these men. The three goals were (1) to attempt to replicate results of the follow-up of the first 223 subjects, (2) to evaluate the potential impact of the quantity and frequency of drinking at the time of the original study on the relationship between LR and alcoholic outcome (ALC), and, most importantly, (3) to test if the relationship between family history (FH) and ALC might be mediated by LR in a subset of the sample. METHODS: Face-to-face structured follow-up interviews were carried out with the subjects and separately with an additional informant, and blood samples, as well as urine specimens, were obtained for determination of state markers of heavy drinking and drug toxicology screens. RESULTS: First, the rate of development of DSM-III-R abuse and dependence on alcohol was 14.1% and 28.6%, respectively, for family history positive (FHP) subjects, compared with 6.6% and 10.8%, respectively, for family history negative (FHN) men. Second, neither consideration of the quantity nor the frequency of drinking at the time of the original study, nor their combination, effectively diminished the relationships between LR and ALC. Third, among men who drank and demonstrated the 15% highest and lowest scores of LR at about the age of 20 years (ie, 30% of the relevant population), the correlation between FH and ALC was greatly reduced when LR was considered, but the correlation between LR and ALC was not greatly diminished when the impact of FH was evaluated. CONCLUSIONS: In this sample of moderately functional white men, the development of alcoholism occurred in relationship to an FH of alcoholism, but alcohol abuse or dependence was unrelated to prior psychiatric disorders. For this group, LR at the age of 20 years was associated with future alcoholism in a manner that was independent of the drinking practices at the time of the original study. At least among those men with clearly high and low LR scores, these data are consistent with the conclusion that LR might be a mediator of the alcoholism risk.

Plasma cortisol levels following ethanol in sons of alcoholics and controls.

We used the pattern of change in plasma cortisol level following ethanol challenges to help characterize differences in response to alcohol in sons of alcoholics and controls. Thirty healthy, drinking young adult sons of alcoholics were matched with 30 sons of nonalcoholics on demography, drug use, and alcohol use histories. Each was tested on three occasions, when he received, in random order, placebo, 0.75 mL/kg of ethanol, and 1.1 mL/kg of ethanol. Subsequent blood samples for cortisol determinations were obtained every 30 minutes over the next four hours. The sons of alcoholics, at higher risk for the future development of alcoholism, demonstrated lower cortisol levels after drinking. The data are consistent with our prior measures of self-reported feelings of intoxication and family group differences in ethanol-induced decrements in performance.

Platelet monoamine oxidase activity in relatives of alcoholics. Preliminary study with matched control subjects.

Platelet monoamine oxidase (MAO) activity levels were determined before and 180 minutes after ingestion of ethyl alcohol in 30 healthy men aged 21 to 25 years. The subjects included 15 men with alcoholic first-degree relatives who were matched by demography, height-weight ratio, and drinking history with 15 control subjects who had no family history of alcoholism. There was a nonsignificant trend toward lower platelet MAO activities at baseline and after ethyl alcohol ingestion in the group with alcoholic relatives when compared with the control subjects who had no family history of alcoholism. With an arbitrary MAO cutoff of 5.24 nmole/mg of protein per hour, eight of the 15 subjects with alcoholic relatives and 12 of the 15 without alcoholic relatives were correctly identified. However, because of the number of false-positive and false-negative findings, the results have limited clinical usefulness.

Major depressive disorder, alcoholism, and reduced natural killer cell cytotoxicity. Role of severity of depressive symptoms and alcohol consumption.

Depression and alcohol abuse have been associated with alterations in cell-mediated immune function. This study directly compared the effects of depression, alcoholism, and their joint contribution to reduce natural killer cell cytotoxicity. Natural killer cell activity was significantly lower in both depressed (n = 18) and alcoholic (n = 19) patients compared with control subjects (n = 50). In addition, patients with a dual diagnosis of either alcohol abuse and secondary depression (n = 9) or depression with a history of alcohol abuse (n = 26) demonstrated a further decrease in natural killer cell activity compared with that found in patients with either depression or alcoholism alone. While both depression and alcoholism are separately associated with a reduction of natural killer cell activity, subgroups of patients in whom the diagnoses of alcoholism and depression coexist show a further decrement in natural killer cell function.

Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism.

BACKGROUND: Alcoholism and substance dependence frequently co-occur. Accordingly, we evaluated the familial transmission of alcohol, marijuana, and cocaine dependence and habitual smoking in the Collaborative Study on the Genetics of Alcoholism. METHODS: Subjects (n=1212) who met criteria for both DSM-III-R alcohol dependence and Feighner definite alcoholism and their siblings (n=2755) were recruited for study. A comparison sample was also recruited (probands, n=217; siblings, n=254). Subjects were interviewed with the Semi-Structured Assessment for the Genetics of Alcoholism. The familial aggregation of drug dependence and habitual smoking in siblings of alcohol-dependent and non-alcohol-dependent probands was measured by means of the Cox proportional hazards model. RESULTS: Rates of alcohol, marijuana, and cocaine dependence and habitual smoking were increased in siblings of alcohol-dependent probands compared with siblings of controls. For siblings of alcohol-dependent probands, 49.3% to 50.1% of brothers and 22.4% to 25.0% of sisters were alcohol dependent (lifetime diagnosis), but this elevated risk was not further increased by comorbid substance dependence in probands. Siblings of marijuana-dependent probands had an elevated risk of developing marijuana dependence (relative risk [RR], 1.78) and siblings of cocaine-dependent probands had an elevated risk of developing cocaine dependence (RR, 1.71). There was a similar finding for habitual smoking (RR, 1.77 in siblings of habitual-smoking probands). CONCLUSIONS: Alcohol, marijuana, and cocaine dependence and habitual smoking are all familial, and there is evidence of both common and specific addictive factors transmitted in families. This specificity suggests independent causative factors in the development of each type of substance dependence.

Alcoholism and genetics: possible biological mediators.

This paper attempts to make a limited number of points: First, there are enough data indicating a probable genetic propensity in alcoholism to justify prospective studies. Second, such studies are a logical way to attempt to differentiate between factors which predispose an individual towards alcoholism and those biological and psychological changes which result from many years of heavy drinking. Third, this type of approach can be used in biological, psychological, or sociological spheres. Because this type of research is relatively expensive and time-consuming, we have attempted to gather information on as many relevant factors as possible, making our final decision about which specific factors are to be tested through a balance of how much sense they make, how easy they are to test, and how well they combine into a test battery. Our present study will not answer questions definitively but will help point us towards those investigations in the future which are most likely to pay off. Other investigators are encouraged to use a similar approach.

EEG fast frequency activity in the sons of alcoholics.

The EEGs of young (21-25-year-old) sons of alcoholics and their matched controls (n = 24 pairs) were computer evaluated to assess activity in the 12-20 Hz (beta) range. Subjects were blindly exposed to ethanol and placebo drinks while EEG was gathered at baseline and 90 min postconsumption. Men with alcoholic fathers [family history positive (FHP)] displayed significantly more beta activity at 90 min postethanol consumption than the men who had no alcoholic relatives [family history negative (FHN)]. In addition, when subjects were sorted into "low" and "moderate" drinkers depending on their drinking practices, additional differences were found between groups. Within the FHN subjects, moderate drinkers were found to have significantly more energy in the beta frequencies at both baseline and at 90 min postdrug than low drinkers. However, though family history positive subjects had overall increases in 12-20 Hz activity compared with the FHN subjects, no significant differences were found between moderate and low drinkers within the FHP population. Taken together, these studies suggest that drinking practices and a familial history for alcoholism can modify the beta content of the EEG in the 12-20 Hz range in young men.

Adrenocorticotropin hormone response to diazepam in healthy young men.

The effects of diazepam (DZ) infusions on changes in adrenocorticotropin hormone (ACTH) are a source of debate. In this study, 66 healthy young adult men were evaluated for changes in plasma ACTH after intravenous infusions with placebo, 0.12 mg/kg and 0.20 mg/kg of DZ. After the higher DZ dose, 85% of the subjects demonstrated a decrease in ACTH of 20% or more, with the nadir occurring between 30 and 60 min postinfusion and values returning to baseline levels by 180 min. These results support the conclusion that at the clinically relevant doses used here, DZ infusions are associated with a significant decrease in ACTH.

Ethanol-related prolactin responses and risk for alcoholism.

Serum prolactin (PRL) levels after drinking 0.75 ml/g of ethanol were observed in 44 nonalcoholic young men who had an alcoholic first-degree relative and 44 controls lacking a family history of alcoholism. The data reveal a significant increase in PRL by 30 min with a return to base line for the family history negative (FHN) men by 90 min but a further decline until 150 min for the family history positive (FHP) individuals. The interaction between family history status and time for prolactin was significant at the p = 0.008 level and the changes in this hormone after drinking was significant for both groups at the p less than 0.0001 level. These results are consistent with an effect of a moderate dose of ethanol on PRL levels and further characterize differences in reactions to ethanol for men at higher and lower risk for the future development of alcoholism.

TSH response to TRH and family history of alcoholism.

The thyrotropin (TSH) response to intravenous thyrotropin-releasing hormone (TRH) was evaluated in 10 sons of alcoholic fathers (FHP group) and 10 matched controls (FHN group). No differences were observed between the two groups in basal TSH, peak TSH levels, on the incidence of TSH-blunting to TRH. Though there was a trend for a less intense TSH response over time after the TRH infusion, the difference between the family groups was not significant. These results are not consistent with some previous reports of an increased percentage of blunted TSH response to TRH for children of alcoholics. The clinical and research implications of these findings are discussed.

P300 latency after ethanol ingestion in sons of alcoholics and in controls.

The magnitude and persistence of ethanol-induced increases in the latency of the P3 event-related potential from auditory stimuli were evaluated in 21 sons of alcoholic fathers (FHP) and 21 control sons of nonalcoholics (FHN) matched on demography and drinking history. The men were assessed at baseline, 70 min after imbibing a beverage, and 240 min after drinking, with observations carried out for each individual in 3 dosage conditions (placebo, 0.75 ml/kg of ethanol, and 1.1 ml/kg of ethanol). There were no family group differences for baseline (prechallenge) P3 latencies, nor any significant group differences after placebo or low-dose ethanol challenges. However, in the high alcohol dose challenge condition, P3 latencies for FHP subjects returned toward baseline measures more quickly than for FHN men. These results are consistent with previous reports of behavioral and biochemical measures in which FHP subjects demonstrated less intense reactions or returned toward baseline conditions more rapidly after ethanol ingestion relative to the FHN controls.

Platelet monoamine oxidase activity levels in subgroups of alcoholics: diagnostic, temporal, and clinical correlates.

Platelet monoamine oxidase (MAO) activity levels were measured in 47 male inpatient alcoholics to determine whether this biological marker might be useful in differentiating subtypes of alcoholics. Of the subgrouping methods tested, only type 2 alcoholics defined by the criteria of Gilligan et al had significantly lower platelet MAO activity than type 1 alcoholics at intake, but this finding was not stable over time in a subset of subjects. Neither separating male veteran alcoholics into either of two other variations of the type 1/type 2 subtypes, nor classifying the sample into primary alcoholics versus primary ASPD with secondary alcoholism categories, yielded significant differences between subgroups. Generally, enzyme activity levels (Vmax) were higher about 10 days after stopping drinking compared to platelet MAO values determined in thrombocytes obtained after approximately 4 weeks abstinence; these levels remained relatively stable 3 months later in a cohort of subjects. Tobacco smoking was significantly negatively correlated to platelet MAO activity levels.

Dopamine-beta-hydroxylase activity levels in men at high risk for alcoholism and controls.

Plasma DBH activity levels were determined for 22 nonalcoholic young men with alcoholic close relatives (the FHP or family history positive group) and results compared to family history negative (FHN) controls matched on demography, height/weight ratio, and drinking history. These enzyme levels were then correlated with the usual drinking history over the prior 6 months and with the intensity of intoxication achieved after drinking 0.75 ml of ethanol/kg body weight. The FHP men demonstrated a 20% lower level of DBH (p greater than 0.1) indicating no significant difference between the groups. Base-line DBH activities correlated significantly with the level of intoxication for the FHN group (r = 0.44, p less than 0.025) with a trend for an inverse correlation with the average drinking history. FHP men, on the other hand, demonstrated only a nonsignificant association between peak intoxication level and base-line DBH and a positive correlation (r = 0.37, p less than 0.05) with the average number of drinks/drinking day. These results are not consistent with the probability that a premorbid DBH assay could be used as one indicator of propensity towards alcoholism. The differences between FHP and FHN groups on correlations between DBH and peak intoxication or usual drinking history raise speculations that the "normal" (FHN) relationship between alcohol intake and plasma DBH activity may be impaired in individuals at high risk (FHP) for the future development of alcoholism.

Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study.

BACKGROUND: The vulnerability to alcohol dependence appears to be genetically influenced through a variety of mechanisms. One potentially genetically mediated channel may be a low level of response (LR) to alcohol, which has been seen in children of alcoholics and noted to predict future alcohol abuse and dependence. This pilot study uses a case and control genetic association approach to evaluate the possible role of five genotypes in both LR and alcoholism in informative subgroups of men with high and low LR scores documented 15 years earlier. METHODS: As part of a larger study, 41 men, about 39 years old, were selected from among the first 113, completed 15-year follow-ups in a prospective study. The 17 subjects whose LRs at age 20 were in the lower third were compared on five polymorphisms of four genes with 24 men whose reactions to alcohol had been above the median. RESULTS: The 14 men with the LL genotype of the serotonin transporter (5-HTT) polymorphism and the seven with the Pro/Ser genotype of the GABAA alpha 6 polymorphism had demonstrated lower LR scores at about age 20, and had significantly higher proportions of alcoholics than the other genotypes for those loci. All four subjects with combined LL and Pro/Ser genotypes had developed alcoholism and demonstrated the lowest LR scores overall. There was no evidence that two polymorphisms of the 5-HT2A receptor gene and one of the 5-HT2C receptor gene were related to LR or alcoholism in this sample. CONCLUSIONS: These results are consistent with animal and human studies suggesting a possible role for genetic variation in the GABAA alpha 6 and the serotonin transporter in the reaction to alcohol and the alcoholism risk.