Differences in the peripheral levels of beta-endorphin in response to alcohol and stress as a function of alcohol dependence and family history of alcoholism

BACKGROUND: Evidence indicates that both genetic and environmental factors, such as stress, may play an important role for the development of alcoholism, while beta-endorphin may be implicated in the control of alcohol consumption. The objective of the present studies was to test the hypothesis that there are differences in the response of the pituitary beta-endorphin system to stress as a function of family history of alcoholism and alcohol dependence. METHODS: The response of the pituitary beta-endorphin to a placebo or an alcohol (0.50 g ethanol/kg) drink and to a stress task performed 30 min following ingestion of either the placebo or the alcohol drink was measured in social and heavy drinkers with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism. Thus, each subject participated in 4 experimental sessions given on different days in a randomized order. Four groups of subjects were investigated: 1) low risk nonalcoholics (LRNA); 2) high risk nonalcoholics (HRNA), 3) low risk alcoholics (LRA); and 4) high risk alcoholics (HRA). Plasma beta-endorphin was estimated prior to and for 3.5 hr post-stress. Changes in the concentration of plasma beta-endorphin following ingestion of either the placebo or alcohol drink without performance of the stress task served as controls to compare the stress-induced changes. RESULTS: Basal plasma beta-endorphin levels were higher in LRNA than LRA, HRNA and HRA participants, while basal plasma beta-endorphin levels were higher in LRA than those in HRNA and HRA participants. Furthermore, there was no significant difference in the plasma beta-endorphin levels between HRNA and HRA participants. Stress, induced a significant increase in plasma beta-endorphin concentration in all four groups of participants. However, the stress-induced increase in plasma beta-endorphin levels was more pronounced in LRNA than HRNA, LRA and HRA participants. Thus, alcohol dependence decreased the basal plasma beta-endorphin levels in LR only, as well as the stress induced increase in plasma beta-endorphin levels of participants without, but not of those with, a family history of alcoholism. Alcohol prior to stress attenuated the stress-induced increase in plasma beta-endorphin levels of all four groups of participants. CONCLUSIONS: The present data indicates that there are differences in both, the basal plasma beta-endorphin levels as well as the response of the pituitary beta-endorphin to stress as a function of family history of alcoholism and alcohol dependence. Thus, in HR individuals a dysfunction in the activity of the pituitary beta-endorphin system predates the development of alcoholism, while in LR individuals it develops following alcohol dependence. Furthermore, alcohol dependence did not alter the alcohol-induced attenuation of beta-endorphin response to stress.     

Differences in the responses of the pituitary beta-endorphin and cardiovascular system to ethanol and stress as a function of family history

BACKGROUND: Genetic and environmental factors, such as stress, are important for the initiation and maintenance of heavy drinking, whereas beta-endorphin may be important in controlling alcohol consumption. These studies investigated the response of pituitary beta-endorphin to stress and the effect of alcohol on the stress response in subjects at low (LR) and high (HR) risk of alcoholism, as determined from their family history. METHODS: Twenty LR and 20 HR subjects were exposed to stress 30 min after ingestion of either a placebo or an alcohol drink. Plasma beta-endorphin was measured before and for 4 hr after the drink. Changes in the concentration of plasma beta-endorphin after ingestion of the placebo or alcohol drink alone served as controls to compare the stress-induced changes. Pulse and diastolic and systolic blood pressure were also measured. RESULTS: HR subjects presented higher baseline values of pulse and systolic blood pressure and lower plasma beta-endorphin than LR subjects. Stress induced a small increase in cardiovascular activity, whereas alcohol induced a stronger stimulation. Alcohol before stress did not prevent the stress-induced increase in cardiovascular activity. Stress, but not alcohol, increased the plasma beta-endorphin concentration. LR subjects presented a higher stress-induced increase in plasma beta-endorphin and a faster recovery than HR subjects. Alcohol before stress attenuated the stress-induced increase in plasma beta-endorphin in both LR and HR subjects. This attenuation was stronger in LR subjects. CONCLUSIONS: Thus, there are differences in the response of beta-endorphin to stress and the effect of ethanol on stress responses as a function of a family history of alcoholism.     

Effects of stress and alcohol on subjective state in humans

BACKGROUND: There is increasing evidence that stress and hypothalamic-pituitary-adrenal axis activation interact with drugs of abuse and influence drug-taking behaviors. Both studies with laboratory animals and survey data with alcohol users suggest that acute or chronic stressful events increase alcohol intake. One mechanism for the increase in alcohol intake may be that stress alters the subjective effects produced by the drug in ways that enhance the reinforcing properties of alcohol. Therefore, in this study we determined whether an acute social stressor alters subjective responses to ethanol in humans. The stressor was a modified version of the Trier Social Stress Test, an arithmetic task that increases cortisol levels. METHODS: Twenty male volunteers participated in two laboratory sessions, in which they performed the Trier Social Stress Test on one session and no task on the other session, immediately before consuming a beverage that contained ethanol (0.8 g/kg in juice) or placebo (juice alone). Eleven subjects received ethanol on both sessions, and nine subjects received placebo on both sessions. Primary dependent measures were self-report questionnaires of mood states. Salivary levels of cortisol were obtained to confirm the effectiveness of the stress procedure. RESULTS: Stress alone produced stimulant-like subjective effects. In the group who received ethanol, stress increased sedative-like effects and decreased stimulant-like effects. CONCLUSIONS: At this relatively high dose of ethanol, stress increased sedative effects of alcohol and did not increase desire for more alcohol. It is possible that in some individuals, the increased sedative effects after stress may increase the likelihood of consuming more alcohol. The effects of stress on consumption at this, or lower, doses of alcohol remain to be determined.     

Peripheral origin of plasma dopamine

To clarify the peripheral origin of plasma dopamine (DA), we studied the changes in plasma levels of free and conjugated catecholamines after nephrectomy, adrenalectomy, chemical sympathectomy and renal denervation. Nephrectomy markedly increased conjugated DA levels, indicating that plasma DA is rapidly excreted through the kidney and originates outside the kidney. Adrenalectomy reduced plasma total epinephrine (E) to undetectable limits, whereas total norepinephrine (NE) and DA levels remained unchanged. In addition, the subsequent immobilization stress significantly increased both total NE and DA, but not E. Chemical sympathectomy with 6-hydroxydopamine decreased both NE and DA by 66% and 72%, respectively. E level, however, was not affected by sympathectomy. Although the following immobilization stress significantly increased all catecholamines levels, the magnitude of increase in concentrations of NE and DA were much less than that of E. These results suggest that plasma DA is mainly derived from the peripheral sympathetic nerve terminals. However, the renal nerve, one of the sympathetic nerves, did not serve as a source of plasma DA because renal denervation had no effect on plasma DA levels in spite of the marked depletion of free DA in the kidney.     

Increased Plasma Atrial Natriuretic Peptide after Ingestion of Low Doses of Ethanol in Humans

Previous studies have demonstrated that, in human, acute consumption of high doses of ethanol, administered in a large quantity of fluid, with or without volume-loading, induced either a decrease or an increase in the plasma content of atrial natriuretic peptide (ANP)—a substance that has a hypotensive effect. The objective of the present study was to examine the effect of low doses of ethanol (0,0.25, and 0.50 g of ethanoVkg of body weight) administered to six normoten-sive individuals, in a small volume of fluid without prior volume-loading. Before and at various intervals after administration of the placebo or ethanol drinks, heart rate and blood pressure were measured and blood samples were taken for estimation of the plasma ANP, arginine vasopressin, and cortisol contents. Results indicated small changes in blood pressure and heart rate after ingestion of either the placebo or ethanol drinks. On the other hand, a significant increase in the plasma ANP content was observed at 15 min after ingestion of both the 0.25 and 0.50 g of ethanol/kg of body weight doses, but not after the placebo drink. Plasma ANP levels were still elevated at 45 min postethanol intake, but had returned to basal levels at 120 min after the ethanol drink. Interestingly, it was noticed that the higher dose of ethanol (0.50 g) did not induce a higher plasma ANP concentration than the lower dose (0.25 g) of ethanol; however, the plasma ANP content remained elevated for a longer period. Furthermore, the increase in plasma ANP content was not due to ethanol or stress-induced increases in the plasma arginine vasopressin and cortisol contents, because the plasma concentration of these hormones remained either at basal or below basal levels for the duration of the experiment. In conclusion, ingestion of low amounts of ethanol equivalent to 1 or 2 standard drinks induced an increase in plasma ANP content.     

Psychophysiological Effects of Oral Ethanol in Alcoholics and Social Drinkers

The acute and extended effects of ethanol ingestion were examined in five alcoholic subjects, and five "social" drinkers. Six physiological and four subjective report measures were taken before, during and up to 90 min after the ingestion of ethanol in three doses and placebo. Findings showed that alcohol exerted significant dose-related physiological effects in the initial minutes of ingestion, and in extended analyses of physiological and subjective measures in both groups of drinkers. Alcoholics and social drinkers generally did not differ in their physiological responses to alcohol doses and placebo, while some evidence for tolerance to reported euphoric effects of alcohol in the alcoholic subjects was found. The possibility is raised that early physiological responses observed during ethanol ingestion may arise not only from pharmacological effects of the drink, but may also be evidence for conditional predrink responses.     

Effect of anticipatory stress on placebo alcohol consumption in a bar laboratory

Background: Only one laboratory study has examined the relation between stress and alcohol use in an ecologically valid drinking context. In that prior study, drinking was measured after the stressful situation. Objective: To examine the effect of an anticipatory stressor, and trait social anxiety on “alcohol” consumption in a bar laboratory. Methods: College students aged 18 and older (N = 127) in same-sex groups of two or three participants took part in a study that ostensibly examined alcohol’s effect on language fluency. Using a between-subjects design, participants were randomly assigned to a stress or control condition. Participants in the stress condition anticipated giving a stressful speech for the fluency procedure, whereas those in the control group anticipated a nonstressful activity. Before the alleged fluency task, groups could order and consume mixed drinks ad lib in a bar laboratory. No beverages actually contained alcohol, but we used a validated procedure to ensure that participants included in these analyses were deceived. Primary analyses were performed with a hierarchical linear model (HLM) due to a substantial group/modeling effect. Results: Counter to expectations, participants in the control group consumed more placebo alcohol than those in the stress condition. This main effect was moderated by past 3 months’ drinks per week, such that the effect was attenuated (or reversed) among heavy drinkers. No main or interaction effects were observed for trait social anxiety. Conclusions: Some stressors (i.e., those invoking performance anxiety) may decrease consumption. People with higher levels of alcohol involvement might be especially motivated to drink for tension reduction purposes.     

Absence of significant interactive effects of high-dose D-cycloserine and ethanol in healthy human subjects: preliminary insights into ethanol actions at the glycine B site of NMDA glutamate receptors

Background: Ethanol reduces N‐methyl‐d ‐aspartate (NMDA) glutamate receptor function via multiple cellular targets. It is not yet clear whether direct ethanol antagonism of the glycine_B co‐agonist site of NMDA receptors is relevant to this effect. The purpose of this study was to evaluate whether ethanol effects at the glycine_B co‐agonist site was clinically relevant by evaluating some aspects of the psychopharmacologic interactions between the glycine_B partial agonist, d ‐cycloserine (DCS), and ethanol in healthy human subjects. Methods: All subjects completed 4 test days under double‐blind conditions in which DCS or placebo was administered orally prior to ethanol or an ethanol‐tainted placebo drink. Two groups of healthy subjects were studied. A first group of subjects (n = 25) were pretreated orally with DCS 500 mg or placebo 4 hours prior to ethanol (0.8 g/kg, p.o. or placebo) administration. A second group of subjects (n = 20) were pretreated with DCS 1000 mg or placebo prior to ethanol administration. Outcomes included subjective and cognitive responses to the experimental interventions. Results: Predictable ethanol responses were observed in both groups of subjects, although the response to ethanol and the breath alcohol levels, but not plasma alcohol levels, were slightly but significantly lower in the group that received the higher DCS dose. DCS produced mild sedative effects that were greater for the lower than the higher dose. It also produced a mild impairment of verbal fluency without impairing attention. No statistically significant interactions between ethanol and DCS emerged in analyses. However, the combination of ethanol and DCS produced significantly greater impairment than both ethanol or DCS administered alone on a test of verbal fluency and aspects of memory function. Implications: DCS and ethanol both produced sedative and cognitive effects, consistent with their ability to reduce NMDA receptor function. However, the absence of interactive effects observed in this study raises questions about the clinical significance of the glycine_B site as a target for ethanol in the brain at levels of ethanol intoxication associated with social drinking. However, it should be noted that this conclusion is limited to the dependent measures evaluated and the doses of ethanol and DCS studied.     

Effects of chronic graded ethanol consumption on the metabolism, ultrastructure, and mechanical function of the rat heart.

Three sequential sets of ethanolic rats (E) and their matched controls (C) were fed regular chow containing standard vitamins with the ethanol group in each series also receiving a progressively greater alcohol intake for 3 to 6 months: E1 5%, E2 10%, and E3 25% ethanol. Electron microscopy showed swelling of mitochondria, transverse tubules and sarcoplasmic reticulum, dehiscence of intercalated discs and disintegration of myofibrils scattered throughout the ventricular myocardium in E1 and E2 as early as 7 wk after beginning 5% ethanol; in addition, there were clumping of mitochondria and supercontraction of myofibrils in E3. Concomitant with substructural abnormalities in E3, there were slight but significant depressions of cardiac myofibrillar ATPase activity and mitochondrial function. Cardiac catecholamines, hydroxyproline, and total bound glycerol were unchanged. Alteration of isometric contraction of isolated, supported left ventricular papillary muscles occurred initially in E2 and was clearly evident in E3 by significant reduction of duration of systolic active state (time from onset to peak tension), while total tension generated and peak rate of tension rise were not yet disturbed. Extra vitamin supplementation in additional rats drinking 25% ethanol minimally lessened decline in myofibrillar ATPase activity, but otherwise provided no protection. Thus, chronic daily ingestion of graded quantities of ethanol representing 10 to 30% of total calories in well-nourished animals exerted toxic effects on microstructure, metabolism and mechanics of the ventricle. These alterations are postulated to be pertinent to early pathogenesis of clinical alcoholic cardiomyopathy.     

The Anticonvulsant Zonisamide Reduces Ethanol Self-Administration by Risky Drinkers

Objective: The purpose of this study is to examine the effects of zonisamide on ethanol self-administration and subjective effects in risky drinkers using a human laboratory paradigm. Method: We conducted a double-blind, placebo-controlled study of the effects of zonisamide 100 mg on ethanol self-administration and urge to drink in risky drinkers (N = 10) (). Result: During the second hour of a 2-hour self-administration session ethanol consumption was 50% lower in the zonisamide group as compared to the placebo group. Urge to drink was also significantly lower under the zonisamide condition. Conclusion: These results indicate that a single dose of zonisamide reduces urge to drink and the quantity of ethanol self-administered by risky drinkers during their second hour of access to alcohol. Scientific Significance: Zonisamide may help individuals drinking at risky levels reduce their intake of alcohol.     

Histamine as a neuroendocrine regulator of the stress-induced release of peripheral catecholamines

The involvement of hypothalamic histaminergic neurons in the stress-induced release of peripheral catecholamines was studied in conscious, freely moving male rats. Blood samples were obtained via a catheter in a femoral artery. Intracerebroventricular infusion of histamine (HA; 30 micrograms) increased the plasma concentrations of norepinephrine (NE) and epinephrine (E) 3- and 9-fold, respectively. The plasma level of dopamine was not affected. The effect of HA was prevented by prior intracerebroventricular infusion of the H1-receptor antagonist mepyramine (100 micrograms) or the H2-receptor antagonist cimetidine (100 micrograms). Restraint stress applied for 5 min caused an immediate but transient increase in the plasma concentrations of NE and E which were increased 5- and 11-fold, respectively. The plasma level of dopamine was not altered significantly by restraint stress. The effect of stress on NE and E was almost prevented by prior icv infusion of mepyramine or cimetidine. The HA receptor antagonists had no effect on the basal plasma catecholamine level. We conclude that neuronal HA is an important mediator of the restraint stress-induced release of peripheral catecholamines by an action on H1- and H2-receptors within the central nervous system.     

Effects of cocaine, exercise, and resting conditions on plasma corticosterone and catecholamine concentrations in the rat

Cocaine and exercise are both known as stressors, but little is known about the combined effects of these two treatments. In this study, rats under the influence of cocaine (12.5 mg/kg, intraperitoneally [IP]) or saline were exposed to a variety of resting conditions, as well as exercise (running, 26 m/min, 10% grade, for 30 minutes), to evaluate the amount of stress imposed by these conditions as determined by the changes in the plasma concentrations of corticosterone (C) and catecholamines (norepinephrine [NE], epinephrine [E], dopamine [DA]). After injection of saline, resting near the operating treadmill for 30 minutes caused the concentration of C to increase from 0.07 +/- 0.03 to 0.30 +/- 0.05 microgram/mL (P less than .05), compared to the increase to only 0.15 +/- 0.04 micrograms/mL after resting in a cage. This increase due to proximity to the treadmill subsided after 50 minutes. After cocaine, the 30-minute resting values were 0.70 +/- 0.15 (treadmill) and 0.55 +/- 0.13 (cage) (P less than .05), and did not subside after 50 minutes. Cocaine also increased levels of E, NE, and DA above those in saline under all rest conditions. With exercise, the value for C in saline increased to 0.61 +/- 0.18, but, in cocaine, the value went to 0.93 +/- 0.05 (P less than .05). The concentrations of E (946 +/- 74 v 603 +/- 101 pg/mL, cocaine v saline) and NE (1,027 +/- 102 v 440 +/- 153, cocaine v saline) during exercise also were exaggerated by cocaine treatment (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Indomethacin on Resting Cerebral Hemodynamic and During Suctioning in Preterm Neonates

The effect of therapeutic doses of indomethacin versus a placebo on cerebral hemodynamics was studied in nine preterm infants using Doppler ultrasound. Three doses of indomethacin (0.2 mg/kg) induced a significant decrease in the mean frequency compared to the placebo. Heart rate, blood pressure, transcutaneous carbon dioxide tension, and transcutaneous oxygen tension remained stable throughout the study. The changes in mean frequency occurred rapidly and were sustained at significantly diminished levels for at least 1 hour. All infants were mechanically ventilated, and the increase of mean frequency secondary to suctioning was significantly attenuated after each dose of indomethacin as compared to the placebo. The results confirmed that infusion of indomethacin caused a reduction in cerebral blood flow, probably by vasoconstriction of cerebral vessels. Indomethacin also seemed to attenuate the cerebrovascular response to hypercapnia induced by endotracheal suctioning. Even so, and because of the alteration of resting cerebral hemodynamics, we do not support the recommendation that indomethacin should be used prophylactically to prevent patent ductus arterious or periventricular intraventricular hemorrhage.     

Comparison of the impact of melatonin on chronic ethanol-induced learning and memory impairment between young and aged rats

Chronic alcohol exposure causes functional and structural changes in nervous system which have all been associated with learning and memory impairments. Furthermore, alcohol consumption has been shown to alter the pattern of neural cell adhesion molecules (NCAM) which are involved in memory processes. In the current work, we investigated the effects of melatonin on learning and memory deficits induced by alcohol exposure in young and aged rats. A group of young rats (3 months old) were administered ethanol for 45 days and half of them were co-treated with melatonin. Similar treatments were performed in the aged (19 months old) rats. Morris water maze test and passive avoidance task were used to assess cognitive performance. Lipid peroxidation (LPO) and glutathione (GSH) levels were determined to characterize the level of oxidative stress in the hippocampus and cortex. NCAM levels were determined by Western blotting in the hippocampal homogenates. There was a significant elevation in LPO levels and a reduction in GSH levels in aged and alcohol-exposed rats. Furthermore, both young and aged rats displayed some cognitive impairment when given with alcohol for 45 days. Co-administration of melatonin with ethanol significantly reduced LPO and elevated GSH levels while improving the learning and memory deficits induced by ethanol; the aged rats exhibited a greater response to melatonin supplementation. Moreover, melatonin modulated NCAM expression in hippocampus. Present findings indicate that exposure to ethanol induces learning and memory deficits probably by generating reactive oxygen species and downregulating NCAM 180 in hippocampus of aged rats. Melatonin improves learning and memory deficits and the behavioral responses of rats to melatonin supplementation are age dependent.     

Effects of anoxia and graded acidosis on the levels of circulating catecholamines in turtles

We measured circulating levels of catecholamines in painted turtles subjected to anoxia with different degrees of concomitant acidosis at 20 degrees C and in turtles subjected to long-term submergence at 3 and 10 degrees C. Blood levels of both epinephrine (E) and norepinephrine (NE) increased during N2-breathing, N2/CO2 breathing and submergence, with NE generally being present in higher concentrations than E. During submergence at 20 degrees C, anoxic turtles experienced an extreme acidosis and NE levels exceeded 18,000 pg/ml. The greater the degree of acidosis in anoxic turtles the higher were the levels of plasma NE (log [NE; pg/ml] = 1.640 x pHa + 15.776, r = -0.826). Elevation of plasma E under anoxic conditions was more modest and the correlation between plasma E and pHa was less pronounced (log [E; pg/ml] = -0.329 x pHa + 6.069, r = -0.285). Submergence at lower temperatures also resulted in increases in plasma levels of NE, but while plasma E generally increased during anoxia, this elevation was less dramatic than that observed for NE. Exposure of turtles to either mild (6.5% CO2) or severe (14.5% CO2) normoxic hypercapnia resulted in no increase in E and only modest increases in NE. Upon resumption of air-breathing in all of the 20 degrees C protocols, turtles rapidly restored E and NE to control levels. The function of elevated plasma catecholamines during anoxia and acidemia in turtles is unknown but may be important in stimulating respiratory and cardiovascular recovery once air-breathing is resumed. Catecholamines may also play a role in mediating the rise in blood glucose we observed in this study, which may be an important factor in maintaining tissue viability during anoxic stress.     

Single-dose ethanol administration activates the hypothalamic-pituitary-adrenal axis: exploration of the mechanism of action

Activation of the hypothalamic-pituitary-adrenal axis (HPAA) by single-dose ethanol administration, which achieved moderately high blood ethanol levels, was explored in naive rats in order to determine the mechanism of ethanol's activation of the stress axis. Adult male rats received a single dose (3.2 g/kg body weight-1 of a 12% solution of ethanol in physiological saline. The plasma concentration of immunoreactive (ir) adrenocorticotropic hormone (ACTH), beta-endorphin (BE) and corticosterone (CS) was determined by radioimmunoassay, whereas, plasma concentrations of epinephrine (E) and norepinephrine (NE) were quantified following reverse-phase liquid chromatographic separation and amperometric detection. Ethanol induced maximal plasma ACTH levels within minutes, which declined toward basal levels by 60 min, whereas, plasma concentration of CS rose rapidly and remained elevated at 60 min. Plasma ACTH and CS levels in saline-treated control animals did not vary significantly at any time point. Consistent with co-release of ACTH from corticotrophs, the plasma concentration of ir-BE increased 5-fold at 15 min and declined towards basal levels at 60 min after-ethanol challenge. Plasma E increased 10- to 20-fold as compared to saline controls or preinjection levels and returned to preinjection levels by 90 min, in a manner similar to ethanol-induced changes in proopiomelanocortin-derived peptides and CS. Removal of the adrenal medulla and thus the source of E prior to ethanol administration, did not attenuate activation of the HPAA. Passive immunoneutralization of arginine vasopressin (AVP), using a high-titer AVP antiserum and a protocol which was found to block ether-induced ACTH secretion by 40% in adult male rats, failed to even partially block ethanol-induced ACTH or CS secretion. The results of this study indicate that neither adrenal medulla-derived E nor AVP are significant regulators or coregulators of corticotroph secretions following a moderately high, single-dose, intragastric administration of ethanol.     

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

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.     

Cardiac function at rest and during exercise in early and late alcohol intoxication

Seven healthy men, aged 21 to 30 years, were investigated by radionuclide cardiography at rest and during submaximal exercise at heavy (early) and during declining (late) alcohol intoxication. Control studies, in which alcohol was substituted by an isocaloric, isovolumic drink, were performed on a different day. The left ventricular ejection fraction at rest decreased from 59 to 56% during early intoxication (serum ethanol 35 +/- 6 mmol/l), whereas no change was observed in the ejection fraction during exercise. No significant change was recorded in stroke volume after alcohol consumption as opposed to a small increase after ingestion of the caloric drink. Plasma noradrenaline concentrations were elevated during exercise and early intoxication. During late intoxication (serum ethanol 21 +/- 5 mmol/l) the left ventricular ejection fraction at rest was increased by 7% compared with the baseline value. At rest the heart rate was increased from 68 +/- 7 to 84 +/- 15 beats/min, whereas cardiac output had reverted to the baseline value. Plasma noradrenaline at late intoxication was increased both at rest and during exercise compared with the baseline values. Apart from tachycardia and a reduction in left ventricular volumes during late intoxication no alcohol induced hemodynamic changes occurred during exercise.     

Stress and alcohol

Alcohol's role in the relief of stress is reviewed. Limitations are observed in recent studies of alcohol and stress. Where stress has been viewed as synonymous with anxiety or tension, many potential stressors and stress responses have been unaccounted for or ignored. Stress is distinguished from tension and anxiety, and a "stress reduction hypothesis" of alcohol abuse is suggested in place of the recently prominent "tension reduction hypothesis." Alcohol has been found to be a frequent contributor to increased stress. Stress-relief drinking is concluded to be one of several prominent factors in the etiology of alcohol abuse and dependency. Suggestions are made for research and treatment.     

Effect of ethanol on contraction and relaxation of isolated rat ventricular muscle

The effects of ethanol on myocardial mechanical properties were evaluated in isolated rat ventricular muscle preparations. Ethanol reduced peak developed tension by 6.3% at a concentration of $\text{100 mg}\text{100 ml}$, 11.8% at $\text{200 mg}\text{100 ml}$ and 27.2% at $\text{400 mg}\text{100 ml}$. A similar degree of depression was observed in $\text{d}\text{T}\text{d}\text{t}$. Time to peak tension was slightly shortened, and isometric relaxation rate was increased at a high concentration of ethanol. The resting tension did not change significantly.Despite biochemical data by others suggesting an alcohol induced delay in calcium sequestration by cardiac microsomes, ethanol at concentrations found in human intoxication depressed the systolic performance of isolated muscle preparations but did not prolong relaxation or alter resting tension.