Interaction between Ethanol and Dextroamphetamine: Effects on Psychomotor Performance

The objective of this study was to investigate the interaction between ethanol and dextroamphetamine with regard to psychomotor performance. Twelve healthy, male, paid volunteers, moderate users of ethanol and amphetamines, participated in this study. Ethanol (0.85 g/kg or placebo) was administered over a 30-min interval. Five minutes before the termination of ethanol or placebo ingestion, dextroamphetamine elixir (0.09 mg/kg, 0.18 mg/kg or placebo) diluted in 50 ml of orange juice was administered. Subjects were tested in a single-blind, latin-square, crossover design with each of the following six conditions: placebo ethanol/placebo dextroamphetamine; placebo ethanol/low-dose dextroamphetamine; placebo ethanol/high-dose dextroamphetamine; ethanol/placebo dextroamphetamine; ethanol/low-dose dextroamphetamine; and ethanol/high-dose dextroamphetamine. The variables measured in this study were: subjective rating of ethanol and dextroamphetamine intoxication, accuracy and latency of response in the Simulator Evaluation of Drug Impairment (SEDI task), blood ethanol concentration by breath analyzer, and plasma concentrations of dextroamphetamine by gas chromatography. Results indicate ethanol induced decrements in performance of the skills necessary to drive an automobile were significantly decreased by dextroamphetamine in a dose-response fashion. The administration of dextroamphetamine did not decrease the subjective ratings of ethanol intoxication.     

Effects of Alcohol on Psychomotor Performance of Women: Interaction With Menstrual Cycle

The effects of alcohol on performance were investigated in 10 ovulating young women. Placebo drink and three doses of alcohol were administered in a random order both during follicular and luteal phases of the menstrual cycle. The women had significantly slower verbal information processing rate and poorer visual detection performance during the follicular than the luteal phase of the menstrual cycle. In psychomotor tasks other than tracking. dose-response relationships of alcohol were different during the different phases of the menstrual cycle.     

Harmful Effects of Marihuana Use: Experiences and Opinions of Current and Past Marihuana Users

A sample of 530 marihuana users, classified according to five use patterns (trial users, past users, occasional regular and daily current users), were asked their experiences and opinions with respect to eight areas related to the dangers of marihuana use: experienced harmful effects; potential dangers to self; type of harm caused to others; potential dangers to society; reasons for possibly discontinuing use by current users; reasons for having discontinued use by past users; legal dangers; and types of people whom users would not recommend use marihuana.     

Interaction between Ethanol and Calcium Channel Blockers in Humans

The purpose of this study was to test the hypothesis that pretreatment with Ca2+ channel blockers would antagonize the effects of ethanol intoxication in humans. The Ca2+ channel blockers verapamil and nifedipine were chosen because preclinical research has shown them to decrease certain behavioral effects of ethanol in animals. Sixteen healthy, male, paid volunteers, moderate users of ethanol, participated in the study (six in the verapamil and 10 in the nifedipine paradigms). Gelatin capsules containing verapamil (80 mg, 160 mg, or placebo) were administered orally 90 min before ethanol ingestion; whereas, gelatin capsules containing nifedipine (10 mg, 20 mg, or placebo) were administered 30 min before ethanol ingestion. Ethanol (0.85 g/kg or placebo) was administered over a 30-min interval. Subjects were tested in a single-blind, latin-square, cross-over design with each of the following six conditions: placebo ethanol-placebo blocker, placebo ethanol-low dose blocker, placebo ethanol-high dose blocker, ethanol-placebo blocker, ethanol-low dose blocker, and ethanol-high dose blocker. The variables measured in this study were subjective rating of ethanol intoxication, Addiction Research Center Inventory alcohol scale, heart rate, blood pressure, short-term memory, accuracy and latency of response in the Simulator Evaluation of Drug Impairment task, and blood ethanol concentrations by breath analyzer. Results indicate that pretreatment with either verapamil or nifedipine failed to antagonize the inebriating effects of ethanol including its decremental effects on short-term memory and psychomotor performance.     

Interaction between Ethanol and Stress on ACTH and β-Endorphin Secretion

The intraperitoneal infusion of ethanol (EtoH) (1 g/hr/kg body weight for 3 hr) to intact rats blunted the secretion of adrenocorticotropic hormone (ACTH) and β-endorphin induced by a subsequent 10-min exposure to mild, inescapable electroshocks (1.5 mA; 2 sec; four shocks/min) or by corticotropin-releasing factor (CRF). Conversely, administration of the shocks for 3 hr diminished the pituitary response to an acute i.p. injection of EtoH. While we have previously shown (Rivier C, Vale W Endocrinology 121:1320–1328, 1987) that prolonged stress induces a loss of pituitary responsiveness due to the depletion of pituitary ACTH stores, the infusion of EtoH did not cause statistically significant changes in pituitary ACTH content. In adrenalectomized rats, the infusion of EtoH caused an elevation of ACTH plasma levels that was significantly ( p ≤ 0.01) larger than intact animals. These rats also showed a blunted pituitary response to the acute injection of CRF, possibly because they were already secreting ACTH at a maximal rate. These results support the hypothesis that CRF, stress, and alcohol do not potentiate each other on pituitary ACTH and β-endorphin secretion.     

Investigation of the "Hangover" Effects of an Acute Dose of Alcohol on Psychomotor Performance

Performance on some complex and difficult tasks has been shown to be negatively affected for some time after an acute dose of alcohol has been cleared from the system. However, Dauncey reported impairment of a relatively simple reaction time task 3 hr after a dose of alcohol, when the blood alcohol concentration was at or near 0. This impairment was positively related to the subject's drinking history. A replication using the same task found a linear dose/impairment relationship during intoxication. A second simple reaction time task and a vigilance task showed a trend toward impairment, but only a divided attention task was significantly affected during intoxication. There was no significant effect of dose on any of these tests during a "morning after" session. The results are discussed in relation to the differences in method between Dauncey and this study.     

Effects of Ethanol Feeding on the Interaction of Rat Hepatocytes with Laminin Peptides

Laminin, a complex glycoprotein of the extracellular matrix, contains a number of biologically active sites. These sites are involved in cell growth, attachment, differentiation, and gene expression. Our previous studies have shown that chronic ethanol consumption by rats impairs hepatocyte attachment to various components of the extracellular matrix including laminin. In this study, three synthetic peptides (PA22-2, YIGSR, and RGD) that correspond to three distinct functional sites on the laminin molecule were used to investigate the effect of ethanol consumption on their cognate receptors. Initially, varying concentrations of each peptide were incubated with isolated hepatocytes from ethanol-fed and pair-fed control rats. These hepatocytes were then assayed for the ability to attach to laminin. The results Indicated that all three peptides effectively inhibited laminin-mediated cell adhesion: the degree of inhibition appeared similar between pair-fed controls and ethanol-fed animals. Of the three peptides, PA22-2 showed the most dramatic inhibition of attachment. Therefore, we investigated the ability of hepatocytes to attach directly to PA22-2 itself. Attachment of hepatocytes from ethanol-fed animals to PA22-2 was impaired by 30% after 4 days and 90% by 14 days. Conversely, no significant difference in attachment to the entire laminin molecule was observed in ethanol-fed animals at these early time points. These results indicated that the ethanol-induced impairment of hepatocyte attachment to laminin may be caused by the decreased interaction of hepatocytes with specific functional sites on the laminin molecule and that specific receptors on the hepatocyte may be affected differently. Because laminin has been shown to influence cell proliferation, differentiation, and gene expression, this defect could potentially result in structural and functional changes of the hepatocytes.     

Studies on Ethanol-Brain Catalase Interaction: Evidence for Central Ethanol Oxidation

The purpose of the present investigation was to further study the relationship between ethanol and brain catalase in vivo. Rats were pretreated intraperitoneally (ip) with varying doses of ethanol or saline 30 min prior to administration of cyanamide (0.68 mmol/kg; ip), 4-hydroxypyrazole (1 mmol/kg; ip) or saline. Rat tissues were perfused in situ under ether anaesthesia. Brain catalase activity was measured using the Clark electrode. Results confirmed inhibition of brain catalase activity by cyanamide and 4-hydroxypyrazole. Ethanol protected catalase from cyanamide and 4-hydroxypyrazole inactivation in a dose-related manner. In a second study, homogenates from perfused brains were incubated in the presence of glucose and glucose oxidase with ethanol or saline and cyanamide or saline. Cyanamide was shown to inhibit the catalase activity in vitro in a dose-related manner. Ethanol prevented this inhibition of catalase when added to the incubation medium prior to cyanamide. These data suggest a competition between ethanol and inhibitors for the H2O2-catalase compound. They also confirm the presence and generation of H2O2 in the rat brain in vivo, and overall seem to support the notion that centrally formed acetaldehyde via brain catalase may be responsible for some of the psychopharmacological actions of ethanol.     

Ethanol Drug Interaction with Chlordiazepoxide and Pentobarbital

Drug interactions between ethanol and pentobarbital and ethanol and chlordiazepoxide were investigated utilizing mice. At the peak of oral ethanol (0-4 g/kg), either sodium pentobarbital (1-120 mg/kg) or chlordiazepoxide hydrochloride (2-400 mg/kg) was given intraperitoneally. Blood concentrations of ethanol, pentobarbital, chlordiazepoxide, and its pharmacologically active major metabolites were monitored utilizing either gas chromatography or high performance liquid chromatography. Lethality and loss-of-righting reflex were measured as indexes of behavioral drug interactions. It was evident from the isobolographic plot that the interactions between ethanol and pentobarbital and ethanol and chlordiazepoxide were more than additive. Interaction between ethanol and pentobarbital was greater than that between ethanol and chlordiazepoxide. Furthermore, with increasing ethanol pretreatment the shift in dose-response curves for the loss-of-righting reflex was affected more than the shift in dose-response curves for lethality. Blood concentration monitoring of each drug indicated that the rate of biotransformation of pentobarbital was significantly decreased; sequential biotransformation of chlordiazepoxide was also altered, resulting in a large accumulation of demethylchlordiazepoxide in the blood.     

Interaction of Stress and Ethanol: Effect on β-Endorphin and Catecholamines

To examine the interaction of ethanol (ET) and stress on beta-endorphin and catecholamine (CA) levels, male rats pretreated with ET (3.0 g/kg, i.p.) or saline were immobilized for 30 min and killed 90 min after the initial injection. Stress resulted in (a) an increase in plasma levels of norepinephrine (NE, 243%), epinephrine (E, 175%), beta-endorphin (220%) and corticosterone (CS, 151%) and a decrease in dopamine (DA, 54%); (b) a decrease in hypothalamic NE (15%) and beta-endorphin (33%) levels and an increase E (23%) and DA (58%) levels; (c) a decrease in pituitary beta-endorphin levels in both the neurointermediate (23%) and anterior (131%) lobes. Treatment with ET resulted in: (a) an increase in plasma NE (81%), E (53%), CS (71%), and beta-endorphin (33%) levels and decrease in DA (54%); (b) a decrease in the hypothalamic NE (12%) levels and an increase DA (27%) and beta-endorphin (46%) levels, and (c) a decrease in beta-endorphin (15.5%) in the intermediate lobe of the pituitary. Treatment with ET of stressed animals had only a small effect: (a) in plasma NE, E, CS, and beta-endorphin levels decreased by 30, 31, 14, and 36%, respectively; (b) in the hypothalamus DA levels decreased by 40% and beta-endorphin increased by 71%; (c) in the pituitary beta-endorphin increased in both the intermediate lobe (25%) and anterior (50%) lobes. Thus when the data of the stressed ET-treated group is compared to that of the nonstressed saline injected group, none of the measures differ significantly. These results confirm our earlier work indicating a significant interaction of ET and stress.     

Sleepiness and Ethanol Effects on Simulated Driving

Twelve healthy young men were assessed in each of four experimental conditions presented in a Latin Square design: 8-hr time in bed (TIB) and placebo, 4-hr TIB and placebo, 8-hr TIB and ethanol, and 4-hr TIB and ethanol. After consuming ethanol (0.6 g/kg) or placebo (0900–0930 hr) with 20% supplements at 1030 and 1100 hr, subjects were tested for sleepiness (Multiple Sleep Latency Test at 1000, 1200, 1400, and 1600 hr) and divided attention (1030 hr) performance on day 1, and for simulated driving and divided attention (1000–1200 and 1400–1600 hr) performance on day 2. In the morning testing, with breath ethanol concentrations (BECs) averaging 0.049%, sleepiness was increased, divided attention reaction times increased (on both days), and simulated driving performance was disturbed in the ethanol and 4-hr TIB relative to placebo. Similarly in the afternoon, with BECs averaging 0.013%, the ethanol and 4-hr TIB condition increased sleepiness and disrupted divided attention and simulated driving performance. The results show that sleepiness and low-dose ethanol combine to impair simulated automobile driving, an impairment that extends beyond the point at which BEC reaches zero. They provide a possible explanation for the incidence of alcohol-related automobile accidents at low BECs.     

Biochemical Evidence for an Interaction of Ethanol and Stress: Preliminary Studies

Studies were carried out to examine the interaction of stress and ethanol. Ethanol (0.5 g/kg)-treated, stressed (electric foot shocks) rats exhibited less marked elevations in plasma levels of nonesterified fatty acids and of corticosterone compared to saline-treated stressed subjects. Stress alone markedly elevated these two parameters in plasma. Ethanol treatment alone also resulted in small elevations in both parameters. Results provide support for a significant interaction of ethanol and stress, and might provide some basis for the purported stress-relieving effect of low doses of ethanol.     

Interaction of Dichloromethane and Ethanol in Rats: Toxicokinetics and Nerve Conduction Velocity

The influence of a single combined administration of ethanol (174 mmol/kg per os) plus dichloromethane (1.6, 6.2, or 15.6 mmol/kg p.o.) on blood concentrations of the tested substances and of carboxyhemoglobin, and on nerve conduction velocity was studied in rats. The blood alcohol concentration was not influenced significantly by dichloromethane. The single high dose of ethanol completely inhibited the carboxyhemoglobin concentration increase due to dichloromethane, but did not prevent the dichloromethane-induced decrease of nerve conduction velocity. It produced initially lower, then higher concentrations of dichloromethane in blood than values seen after administration of dichloromethane per se. Rats treated with ethanol plus dichloromethane showed a more pronounced decrease of nerve conduction velocity compared with rats administered dichloromethane only.     

Interaction of Apomorphine and Amantadine with Ethanol in Men

Male moderate drinkers (n = 12) drank ethanol (0.8 g/kg) and then ingested one of the following: apomorphine (5 mg), amantadine (200 mg), or placebo. Subjects were tested on a battery of physiological and behavioral measures using a double-blind, within-subjects, crossover design. Postethanol ingestion of apomorphine significantly increased ethanol's effect on 3 out of the 8 measures employed (divided attention, objective and subjective inebriation ratings) without significantly altering blood ethanol concentrations or the rate of blood ethanol decline. There was no indication that apomorphine antagonized ethanol's effects. In contrast to reports indicating that amantadine antagonized ethanol depression in rodents, amantadine did not significantly alter the degree of ethanol intoxication in humans. The increase in intoxication induced by apomorphine supports suggestions that dopaminergic systems may be involved in mediating ethanol intoxication and that the sobering effect of catecholamine-augmenting drugs results from noradrenergic, rather than combined noradrenergic and dopaminergic, stimulation. Further studies are necessary to elucidate the role of pre- and postsynaptic dopaminergic receptors in mediating these effects.     

Ethanol Effects on Striatal Neuron Activity

Cellular effects of ethanol were investigated in the rat neostriatum with local perfusion and extracellular, single unit recording techniques. Neuronal activity was modulated specifically as a function of ethanol concentration over a wide test range. At extremely low doses (10(-9) and 10(-8) M), the neuronal responses to drug perfusion were exclusively excitatory. However, at the highest doses examined (10(-8) and 10(-4) M), the results were reversed. In the midrange, a number of apparently ineffective tests were obtained, along with bimodal (excitation followed by depression) responses. The unequivocal responsiveness to ethanol at very low concentrations raises the possibility of a physiological role for the endogenous substance.     

Effects of Ethanol, Chlordiazepoxide, and MK-801 on Performance in the Elevated-Plus Maze and on Locomotor Activity

The effects of ethanol, chlordiazepoxide, and MK-801 on performance in the elevated-plus maze and on activity measured in a circular activity monitor were compared in Sprague-Dawley rats to determine whether these effects of ethanol could be explained by its action on either GABA_A or NMDA receptors. Both ethanol and chlordiarepoxide produced an increase in the time spent in the open arms of the elevated-plus maze and in the ratio of open arm to total arm entries, indicative of an anxiolytic action of these drugs. MK-801 did not alter either the time spent in the open arms or the ratio of open to total arm entries. Chlordiazepoxide and MK-801 produced an increase in total arm entries that suggested that these compounds were increasing locomotor activity. Ethanol also increased total arm entries, but the effect was not statistically reliable. Following habituation to an activity monitor, neither ethanol nor chlordiazepoxide increased activity in this task, whereas MK-801 produced a robust increase in locomotion. Additionally, neither ethanol nor chlordiazepoxide blocked the MK-801-induced locomotor stimulation. The latter finding suggests that the effects of ethanol on GABAA receptors was not Mocking an increased activity level produced by its antagonism of NMDA. Additionally, these results indicate that the anxiolytic and locomotor action of ethanol in rats parallel the effects of a benzodiazepine and not those of an NMDA antagonist. Finally, these results suggest that the consequence of ethanol's antagonism of NMDA receptor function is more restricted than that produced by MK-801.     

Effects of Ethanol Intake on Lipoproteins

These review discusses the effects of ethanol on lipoprotein levels and function as related to atherosclerosis and cardiovascular disease (CVD), with special emphasis on recent publications. Ethanol's effects on high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG), and other CVD risk factors recently have been explored. Other new data address genetic and demographic predictors and mechanisms of these responses. Not surprisingly, the results of some recent studies corroborate, whereas others differ from, earlier seemingly well-established findings. Prior and recent evidence shows favorable changes in HDL, other CVD risk factors, and CVD event rates with moderate, regular ethanol intake, and recent publications have explored the mechanisms of this relationship. Application of these findings in clinical practice remains problematic, however, due to the lack of randomized, controlled clinical trials of ethanol and due to the potential hazards of ethanol consumption.     

Brain Stimulation Reward: Effects of Ethanol

This paper briefly describes and compares the effects of ethanol with those of other abuse substances on brain stimulation reward. The most frequently observed effects of abuse substances on this phenomenon is an increase in sensitivity of the animal to the stimulation. This increased sensitivity to rewarding brain stimulation has been studied as a model of drug-induced euphoria. Although many studies have reported that ethanol does increase the sensitivity of animals to this stimulation, there is much less consistency in results between laboratories than observed with the abused opiates or psychomotor stimulants. Data is presented that suggests that associative factors, e.g., self- versus experimenter-administered ethanol, as well as route of administration and time of brain stimulation testing may all contribute to the variability in results obtained between laboratories. Further, the effects of ethanol on brain stimulation reward are more like those of other sedative-hypnotics than the opiates or psychomotor stimulants.     

Ethanol Ingestion and Polyunsaturated Fatty Acids: Effects on the Acyl-CoA Desaturases

The ingestion of ethanol results in altered compositions of the polyenoic fatty acids in a variety of liver and brain membranes. A possible cause for these alterations in hepatic endoplasmic reticulum membranes has been studied by measuring the delta 9, delta 6, and delta 5 acyl-CoA desaturase activities in hepatic microsomes from chronically or acutely treated rats. Chronically, ethanol decreased all three enzyme activities with the following order of sensitivity: delta 6 (65%), delta 9 (54%), and delta 5 (46%). The short-term study indicated that all three desaturase activities were affected after 1 day of ethanol feeding. NADPH- and NADH-cytochrome c reductase activities were found to be reduced in chronically treated rats, and the NADH-cytochrome c reductase was decreased in the acutely treated. However, these reduced enzyme activities could not account for the decrease in desaturase activities due to the very marked differences between the specific activities of these enzymes compared to the desaturase. Thus, we conclude that changes in membrane polyenoic fatty acid composition can be result of ethanol-induced decreases in the terminal desaturase enzymes.