Age of alcoholism onset. II. Relationship to susceptibility to serotonin precursor availability.

Alcoholics who start abusing alcohol early in life have been found to exhibit problems with mood and aggression control more frequently than patients with a later onset of alcoholism. Because alcohol preference and consumption, as well as mood and aggression regulation, are believed to be influenced by serotonin, relationships between tryptophan availability and mood and aggression regulation were explored in alcoholics. When studied in the entire population, the ratio of tryptophan over other amino acids competing for brain entry (which influences brain serotonin) was found to be lowest one day after cessation of drinking and to increase progressively over the following two to three weeks. When the population was divided into two groups of patients according to whether subjects started abusing alcohol before or after 20 years of age, associations between a low tryptophan ratio and depressive and aggressive tendencies were significant only in the subgroup of patients with an early onset of alcoholism. They were not significant in the rest of the population. Our data are compatible with the interpretation that patients with an early onset of alcoholism have a preexisting serotonin deficit that could manifest itself by an increased alcohol intake early in life and by an increased vulnerability to fluctuations in precursor availability.

Acute effects of intravenous infusions of alcohol on baroreceptor sensitivity in essential hypertension.

To assess the acute effects of alcohol on baroreceptor reflex in moderate and heavy drinkers with essential hypertension and in healthy subjects who drank moderately, four groups of age and sex matched subjects were studied. Group 1 consisted of 10 healthy subjects (age range 21-50 (mean 37.4(10.5) years), who usually drank less than 200 g of alcohol per week; group 2 patients (age range 21-50 (mean 37.4(10.3) years) with mild or moderate essential hypertension and whose weekly alcohol consumption was less than 200 g; and groups 3 and 4 patients with mild or moderate hypertension (age range 21-50 (mean 37.2(10.2) years and 21-52 (mean 38.1(10.4) years respectively), who usually drank greater than 700 g of alcohol per week. In groups 1-3 an infusion of alcohol (7 mg.kg-1.min-1) in 500 ml of 5% glucose was administered for 1 h to keep blood concentrations constant (6-7 g.litre-1), whereas in group 4 the dose was doubled (blood concentration 10-11 g.litre-1). Baroreceptor sensitivity was measured by the phenylephrine method before and after alcohol infusion and one or two days later before and after infusion of 500 ml of 5% glucose. In healthy subjects and in moderate drinkers with hypertension the alcohol reduced baroreflex sensitivity significantly (from 17.5(9.5) to 13.8(8.4); p less than 0.01 and from 15(10) to 10.5(6.7) ms.mmHg-1, p less than 0.01 respectively), whereas in the heavy drinkers with hypertension it was significantly reduced only at the highest dose of alcohol (from 12.5(6) to 7.9(3.5) ms.mmHg-1; p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol consumption and hypertension.

An increased prevalence of hypertension in groups with high alcohol consumption has been recognized for a number of years. More recently, several studies have suggested an independent association between alcohol consumption and blood pressure levels in samples from general populations. Of 30 cross-sectional population studies reviewed, the majority reported small but significant elevations in blood pressure in those consuming three drinks or more per day in comparison with nondrinkers. In 25% of studies, elevations in blood pressure were also reported at lower levels of consumption; in about 40%, the blood pressure of nondrinkers was greater than that of those consuming one to two drinks per day. In two studies, one from the United States and one from Australia, the maximum contribution to the prevalence of hypertension of alcohol consumption greater than two drinks per day was estimated to be 5 to 7%; the contribution in men (11%) was greater than that in women because of their greater alcohol consumption. A prospective association of alcohol consumption with change in blood pressure was observed in five studies. In a small number of experimental studies, short-term falls in blood pressure accompanied alcohol restriction in both normotensive and hypertensive subjects. Uncontrolled observations in heavy drinking populations suggest that the effect on blood pressure of alcohol withdrawal may be lasting. However, firm conclusions about the long-term effects of alcohol restriction, particularly in moderate consumers who represent a large proportion in many populations, must await long-term controlled trials.

Antihypertensive effect of alcohol in spontaneously hypertensive rats.

The influence of ethanol (alcohol) consumption on blood pressure during and after the development of hypertension was examined by using spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP). Normotensive Wistar-Kyoto (WKY) rats were also used for comparison. Substituting alcohol (5-20%) for drinking water at 1 month of age retarded the age-dependent rise of blood pressure in all three strains so that, at 7 months, blood pressure measured by a tail-cuff method was 24 mm Hg, 26 mm Hg, and 41 mm Hg lower in the alcohol-treated WKY rats, SHR, and SHRSP, respectively, than in untreated rats. Significant differences in blood pressure were seen in each strain after only 3 months. Withdrawal of alcohol at this stage caused an acute rise of blood pressure then a return to subnormal levels, which persisted for a further 3 months. Administration of 15% alcohol to adult WKY rats and SHR for 2 months had no significant effect on blood pressure. Increasing alcohol content to 20% for a further 2 months prevented rises of blood pressure in both strains. Thus, although continuous drinking of alcohol does not lower blood pressure, it appears to counteract the development of hypertension in rats.

Alcohol, tobacco, and hypertension.

In many studies of diverse populations it has been found that persons drinking relatively large amounts of alcohol tend to have higher blood pressures. In the Kaiser-Permanente study of about 87,000 persons, this alcohol-blood pressure association was not attributable to demographic characteristics, adiposity, reported salt use, smoking, or coffee consumption, nor could it be explained by underreporting of alcohol consumption. If the relationship is a causal one, the pathogenesis is not yet established; direct mechanisms or the effects of withdrawal from alcohol are possible explanations. The Kaiser-Permanente data suggest that about 5% of hypertension in the general population may be due to the consumption of three or more alcoholic drinks per day. Alcohol use shows a positive relation to some sequelae of hypertension but not others; the outstanding exception is coronary heart disease which is negatively related to alcohol intake, probably through different mechanisms. In most studies, cigarette smokers have shown similar or slightly lower blood pressures than non smokers. The degree to which this is due to the thinner body build of smokers, on the average, is not well established; nor is the degree to which a stronger negative relation of smoking to blood pressure might be masked by concomitant alcohol use.

Diminished adrenocorticotropin response to insulin-induced hypoglycemia in nondepressed, actively drinking male alcoholics.

Although changes in hypothalamic-pituitary-adrenal axis function have frequently been reported in alcoholics, the majority of studies have used recently detoxified subjects in whom abstinence phenomena and clinical depression may contribute to observed stress axis alterations. To isolate the primary effects of alcohol dependence on the stress axis, the ACTH and cortisol responses to insulin-induced hypoglycemia were measured in seven actively drinking male alcoholics recruited from the general public through a newspaper advertisement along with eight age-matched male controls. The alcoholic subjects met current American Psychiatric Association diagnostic criteria for alcohol dependence, were stably employed, and had no concurrent psychiatric disorders, cognitive impairment, or psychometric evidence of depression. While relatively young (30.0 yr; range, 22-48 yr), they had lengthy histories of alcohol-related problems (11.9 yr; range, 5-30 yr). Insulin administration resulted in similar nadirs in blood sugar in both alcoholic and control groups. However, the plasma ACTH response was markedly blunted in the alcoholics (P = 0.040, by Mann-Whitney U test). There was a nonsignificant trend toward increased cortisol levels in the alcoholic group. The findings suggest that altered hypothalamic-pituitary-adrenal axis function in alcoholics is a primary results of chronic ethanol exposure rather than a confounding effect of clinical depression or recent detoxification.

Growth hormone response to intravenous diazepam and placebo in 82 healthy men.

Growth hormone (GH) response to placebo and two different doses of diazepam (0.12 mg/kg and 0.20 mg/kg) were evaluated in 82 healthy young men. Both diazepam doses had a significant effect on the growth hormone secretion, with peak values occurring between 30 and 60 min postinfusion, after which levels returned to baseline. There was also a small but significant change in this hormone over time after placebo, but this was reflected by a slow rise following the saline infusion. Individual GH responses to diazepam were variable and, when a cut-off point of 7.5 ng/ml GH increase before 90 min postdrug administration was used, 1% of the men demonstrated a response after placebo, 17% after low-dose diazepam, and 37% following high-dose diazepam. The clinical implications and limitations of these findings are discussed.

Plasma GABA-like activity in response to ethanol challenge in men at high risk for alcoholism.

Sons of alcoholic fathers (high risk, HR) and matched control men from families without alcoholism (low risk, LR) were administered, in a randomized double-blind fashion, either a placebo beverage or an isovolemic beverage containing ethanol (0.8 g/kg). Serial blood sampling for determination of plasma gamma-aminobutyric acid (GABA)-like activity, mood, and intoxication ratings were performed. The HR subjects were found to have significantly less plasma GABA-like activity than LR during the placebo condition. The alcoholic beverage condition washed out the differences in plasma GABA between groups. Significant interactions between risk group status and beverage conditions were found with respect to plasma GABA-like activity. Alcohol produced an increase in mean GABA-like activities among HR subjects, whereas a slight decline was noted among LR subjects. Plasma GABA-like activity also had a significant inverse correlation with self-reports of perceived tension in the placebo condition, and tension, confusion, and intoxication in response to the alcoholic drink. Since previous investigators have reported reduced plasma GABA levels in alcoholic individuals, reduced plasma GABA-like activity may be a biological marker for vulnerability to alcoholism or for heightened tension as a behavioral factor that predisposes to alcoholism.

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.

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.

Social, psychological and physical factors affecting the nutritional status of elderly subjects: separating cause and effect.

The fact that most of the important changes in nutritional status with age are not secondary to aging per se in no way detracts from their importance. This paper reviews three factors that can affect nutritional status in elderly adults: ethanol intake, cognitive status, and institutionalization. The discussion focuses on the difficulties in obtaining reliable information on the interaction of nutritional status with these factors.

Effects of moderate alcohol intake in fixed or variable amounts on concentration of serum lipids and liver enzymes in healthy young men.

To assess the effects of moderate alcohol consumption on fasting serum triglyceride (TG), total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), glutamate-oxaloacetate transaminase (GOT), and gamma-glutamyl transferase (GGT) concentrations, groups of normolipidemic, nonsmoking, nonathletes who were moderate drinkers aged 21-35 y and within 10% of ideal body weight consumed 40 g ETOH/d as beer (fixed drinkers) or maintained usual drinking habits (variable drinkers) for 6 wk, then abstained from all alcohol for 3 wk. A similar group of nondrinkers served as the control group. HDL-C concentrations increased significantly during alcohol consumption and decreased during abstention to initial values in both the variable and fixed drinkers. No significant difference was found between the two drinking groups. LDL-C and TC concentrations in variable drinkers were modestly lower than those in nondrinkers but not in fixed drinkers. No significant differences were found in TG, GOT, and GGT concentrations between the groups or during alcohol consumption or abstention. This study demonstrates that consumption of alcohol in fixed or variable amounts is associated with an increase in HDL-C. This increase is not due to an induction of GGT and GOT as speculated.

Alcohol consumption and nutrient intake in middle-aged Scottish men.

The relation between alcohol consumption and dietary intake was examined in 164 middle-aged Scottish men taking part in a study of risk factors for coronary heart disease (CHD). A 7-d weighed dietary record was used to assess alcohol and nutrient intake. The mean daily intake of alcohol was 26 g (SD 31 g). Energy derived from alcohol tended to replace energy derived from other nutrients and increasing intake of alcohol was associated with a decrease in the amounts of carbohydrate, total fat, and saturated and monounsaturated fatty acids in the diet. Those with a low alcohol intake (0.1-9 g alcohol/d) had a higher intake of total fiber, cereal fiber, polyunsaturated fatty acids, and linoleic acid and a smaller proportion smoked cigarettes. The differences are small but may contribute to the lower mortality from CHD reported by other studies in those with a low alcohol intake.

Moderate alcohol intake and spontaneous eating patterns of humans: evidence of unregulated supplementation.

Alcohol's effects on eating were investigated by paying 92 adult humans to maintain 7-d diaries of everything they ingested, the time of ingestion, their subjective state at the time of ingestion, and the number of people present at the time of ingestion. Total intakes, meal sizes, meal compositions, pre- and postmeal intervals, and deprivation and satiety ratios were compared between nondrinkers and drinkers and between meals associated with alcohol ingestion and those without. Univariate and multivariate prediction of meal size and of postmeal interval were also calculated to ascertain alcohol's contribution to the regulation. The results suggest that alcohol supplements rather than displaces macronutrient-supplied calories, that alcohol is associated with prolonged meal durations, and that alcohol calories may be unregulated. Other apparent changes in the meal pattern appear to be artifacts of time of day and meal duration.

Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective.

From a genetic standpoint, humans living today are Stone Age hunter-gatherers displaced through time to a world that differs from that for which our genetic constitution was selected. Unlike evolutionary maladaptation, our current discordance has little effect on reproductive success; rather it acts as a potent promoter of chronic illnesses: atherosclerosis, essential hypertension, many cancers, diabetes mellitus, and obesity among others. These diseases are the results of interaction between genetically controlled biochemical processes and a myriad of biocultural influences--lifestyle factors--that include nutrition, exercise, and exposure to noxious substances. Although our genes have hardly changed, our culture has been transformed almost beyond recognition during the past 10,000 years, especially since the Industrial Revolution. There is increasing evidence that the resulting mismatch fosters "diseases of civilization" that together cause 75 percent of all deaths in Western nations, but that are rare among persons whose lifeways reflect those of our preagricultural ancestors.

Effect of prenatal alcohol exposure on growth and morphology of offspring at 8 months of age.

In this prospective study of alcohol and other substance use during pregnancy, a cohort of women was interviewed at each trimester of pregnancy and when the offspring were 8 months of age. Data are presented concerning the outcome for 461 infants. A significant relationship was found between alcohol use during pregnancy and the growth and morphology of the offspring at the 8-month follow-up observation. Alcohol use during the second and third trimesters of pregnancy and continuous use of alcohol throughout pregnancy were significantly related to lower weight, length, and head circumference in the exposed infants at the follow-up observation. A significant increase in the risk of minor physical anomalies and fetal alcohol effects was also predicted by prenatal alcohol exposure.

Effects of moderate alcohol consumption on platelet function, tissue-type plasminogen activator and plasminogen activator inhibitor.

Short-term effects of moderate alcohol consumption on platelet function, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) were studied in two age groups of volunteers (20-30 and 45-55 years), each consisting of eight healthy males. The alcohol (30 g in red port and wine) was consumed during a standard dinner. Two blood samples were drawn: one in the postprandial phase, and one the next morning after fasting overnight. Alcohol consumption tended to increase platelet aggregation and production of hydroxy fatty acids, reduced plasma t-PA activity and increased PAI activity in the postprandial phase. After the overnight fast the effects on t-PA and PAI had disappeared whereas at that time alcohol consumption tended to decrease platelet function. The effects of alcohol on t-PA and PAI activity appeared mainly in the older age group, whereas the t-PA activity in this group was already much lower, irrespective of alcohol consumption.

Ethanol metabolism in heavy drinkers after massive and moderate alcohol intake.

Some alcoholics have a regular daily alcohol consumption of more than 100 g. In preliminary observations we had the impression that the claimed alcohol intake in such 'heavy drinkers' was higher than could be accounted for by the ethanol elimination rate as measured routinely at 10 mmol/l (0.5 g/l). We therefore measured the ethanol elimination rate at very high blood ethanol concentrations of 40-80 mmol/l (2-4 g/l) found in eight alcoholics following heavy alcohol intake by measuring the falling blood ethanol concentrations until being less than 1 mmol/l. The elimination rate, on average 83 mumol/min per 1 blood, was about 49% higher than the elimination rate measured at 10 mmol/l in the same subject, being on average 58 mumol/min per 1/blood (paired t-test, P less than 0.05). The elimination rate following the high initial ethanol concentrations remained high until the concentration was below 5 mmol/l. Calculations of elimination rates are based on a number of assumptions concerning the physiologic and metabolic conditions. We examined specifically if the concentration-time curves could be adequately described by assuming metabolism according to a Michaelis-Menten pathway with a low Km value (simulating alcoholdehydrogenase with Km 0.2 mmol/l) or by assuming metabolism by two pathways with an alternative high-Km pathway with Km about 10 mmol/l. It was not necessary, in the statistical analysis, to include an alternative high-Km pathway. On the other hand, the data does give room for up to 50% elimination via such alternative pathways. The elimination rate at the high concentrations corresponded roughly to the claimed daily alcohol intake; furthermore the measured elimination rate at the lower concentrations were similar to values in non-alcoholics.

Taste reactivity to alcohol in rats.

Rats were infused intraorally with 4 concentrations of ethanol (3%, 6%, 9%, and 12%), and their subsequent oral, facial, and bodily responses were videotaped and analyzed. Naive rats did not display significant changes in ingestive-type responding over the concentrations tested. A significant increase in aversive responses was noted, with the largest number of aversive responses found with the 12% solution. Initial reactivity failed to predict subsequent consumption when rats were given free access to the same alcohol concentrations during 2-bottle tests. Reactivity testing after the period of alcohol access indicated that only the aversive responding changed significantly from the initial reactivity, with rats showing fewer aversive responses. The results indicated how the taste of alcohol is perceived by naive rats and how this perception is changed after consummatory experience with alcohol.

Alcohol aversion generalization in rats: specific disruption of taste and odor cues with gustatory neocortex or olfactory bulb ablations.

Rats with ablations of the gustatory neocortex (Experiment 1) and rats with olfactory bulb ablations (Experiment 2) were compared with normal rats for aversion generalization to both single taste solutions (sucrose, sodium chloride, quinine hydrochloride, hydrochloric acid) and compound taste solutions (pairs of the four single tastants) following alcohol aversion training. All rats acquired equal and strong alcohol aversions. Control rats showed consistent aversion generalization to both the sucrose + quinine and the sucrose + hydrochloric acid solutions; no significant generalization occurred to the single tastants except a weak generalization to sucrose in Experiment 2. Rats with gustatory neocortical ablations failed to show aversion generalization to any of the taste solutions. Rats with olfactory bulbectomies displayed the same aversion generalization functions as control rats but exhibited significantly faster extinction of the alcohol aversion than did the trained control rats. Results from the present experiments suggest that during alcohol aversion learning, rats lacking gustatory neocortex use odor cues (no taste generalization), whereas rats lacking olfactory bulbs utilize taste cues (normal taste generalization).