Effects of a moderate evening alcohol dose. II: performance

BACKGROUND: This second of a pair of papers investigates the effects of a moderate dose of alcohol and staying up late on driving simulation performance and simple visual reaction time (RT) at a known circadian phase in well-rested young adults. METHODS: Twenty-nine adults (9 males), ages 21 to 25 years, spent 1 week on an at-home stabilization schedule of 8.5 to 9 hours, followed by 3 nonconsecutive nights in-lab: adaptation, placebo, and alcohol. Performance task practice occurred on 3 occasions before the study. Alcohol (vodka; 0.54 g/kg men; 0.49 g/kg women mixed with tonic) was consumed over 30 minutes ending 1 hour before normal bedtime; the same quantity of beverage was given on placebo. Driving simulation (with drive-only and dual-task drive and subtract components) and psychomotor vigilance task (PVT) testing occurred before and after alcohol/placebo ingestion. Breath alcohol concentration (BrAC) readings were taken before all test sessions. Saliva samples were taken approximately every 30 minutes to determine circadian phase. RESULTS: Driving simulation and PVT variables significantly deteriorated with increasing time awake. Driving simulator lane variability was worse with alcohol compared with placebo at 15.5 hours awake. No PVT variable showed an effect of alcohol. CONCLUSIONS: Driving simulation performance deteriorated with extended waking and with alcohol; driving was most impaired at the peak alcohol level. The PVT, less complex than the driving simulation, did not show effects of alcohol, a finding consistent with previous literature that disruptive effects of low alcohol concentrations increase with task complexity. Overall, simulated driving performance is significantly impaired late at night when even a moderate dose of alcohol is consumed.     

Influence of alcohol on cognitive performance during mild hypoglycaemia; implications for Type 1 diabetes.

AIMS: Alcohol and hypoglycaemia independently affect cognitive function. This may be relevant for insulin-treated diabetic patients who drive motor vehicles. The aim of this study was to examine the effect of mild hypoglycaemia (2.8 mmol/l) with modest alcohol intoxication (levels below UK driving limits) on intellectual performance in patients with Type 1 diabetes. METHODS: A hyperinsulinaemic glucose clamp (60 mU/m2) was used to study 17 subjects [age 35 +/- 8 years, HbA1c 8.1 +/- 1.4% (mean +/- sd)] on four occasions: (A) euglycaemia (4.5 mmol/l) with placebo, (B) euglycaemia with alcohol, (C) hypoglycaemia (2.8 mmol/l) with placebo, and (D) hypoglycaemia with alcohol. Cognitive performance was assessed using four-choice reaction time (4CRT, primary outcome), measurements of general intellectual skills [trail making B (TMB) and digit symbol substitution (DSST)], and visual information processing [visual change detection (VCD)]. A test related to driving performance (hazard perception) was also used. RESULTS: In experiments B and D the average blood alcohol level was 43 mg/dl. This was associated with deterioration in 4CRT [+ 35 ms [95% confidence interval (CI) 20, 50]] and TMB, whereas hypoglycaemia without alcohol increased 4CRT only [+ 39 ms (95% CI 5, 73)]. However, when alcohol was combined with hypoglycaemia, there was marked deterioration in all the cognitive function tests [4CRT 74 ms (95% CI 35, 113), TMB, DSST and VCD]. Hazard perception was not affected. The effect of alcohol was no different in euglycaemia than in hypoglycaemia, i.e. there was no interaction. Whereas hypoglycaemia did not reduce the likelihood that the subjects would drive, alcohol did. CONCLUSIONS: The cumulative effect of alcohol and hypoglycaemia on cognitive function together has implications for driving in patients with Type 1 diabetes. Both independently impair cognitive function and together the effects are additive. Patients with Type 1 diabetes should be educated about hypoglycaemia and driving and should avoid alcohol completely if planning to drive.     

Kudzu extract treatment does not increase the intoxicating effects of acute alcohol in human volunteers

Background: Isoflavone administration in the form of a purified extract from the herbal medication kudzu root has been shown to reduce, but not eliminate, alcohol consumption in alcohol‐abusing and alcohol‐dependent men. The precise mechanism of this action is unknown, but 1 possible explanation for these results is that the isoflavones in kudzu might actually increase the intensity or duration of alcohol’s effects and thus delay the desire for subsequent drinks. This study was designed to test this hypothesis. Methods: Twelve (12) healthy adult men and women (27.5 ± 1.89 years old) who consumed moderate amounts of alcohol (7.8 ± 0.63 drinks/wk) participated in a double‐blinded, placebo‐controlled crossover study in which they were treated with either kudzu extract (total isoflavone dose of 750 mg/d) or matched placebo for 9 days. On days 8 and 9, participants received an acute challenge of ethyl alcohol (either 0.35 or 0.7 g/kg alcohol). During the challenges, the following measures were collected: subjective effects, psychomotor (body sway), cognitive performance (vigilance/reaction time), physiological measures (heart rate and skin temperature), and plasma ethanol concentration. Results: Alcohol resulted in a dose‐related alteration in subjective measures of intoxication, impairment of stance stability, and vigilance/reaction time. Kudzu extract did not alter participants’ subjective responses to the alcohol challenge or to alcohol’s effects on stance stability or vigilance/reaction time. However, individuals treated with kudzu extract experienced a slightly more rapid rise in plasma ethanol levels, but only after the 0.7 g/kg dose. This transient effect during the first 30 minutes of the ascending plasma alcohol curve lasted only 10–15 minutes; there were no differences in peak plasma alcohol levels or alcohol elimination kinetics. Additionally, kudzu pretreatment enhanced the effects of the 0.7 g/kg dose of alcohol on heart rate and skin temperature. Conclusions: These data suggest that individuals who drink alcohol while being treated with kudzu extract experience no adverse consequences, and furthermore the reported reductions in alcohol intake after kudzu extract treatment are not related to an alteration in alcohol’s subjective or psychomotor effects.     

Effects of Alcohol on Performance on a Distraction Task During Simulated Driving

Background:  Prior studies report that accidents involving intoxicated drivers are more likely to occur during performance of secondary tasks. We studied this phenomenon, using a dual-task paradigm, involving performance of a visual oddball (VO) task while driving in an alcohol challenge paradigm. Previous functional MRI (fMRI) studies of the VO task have shown activation in the anterior cingulate, hippocampus, and prefrontal cortex. Thus, we predicted dose-dependent decreases in activation of these areas during VO performance.
Methods:  Forty healthy social drinkers were administered 3 different doses of alcohol, individually tailored to their gender and weight. Participants performed a VO task while operating a virtual reality driving simulator in a 3T fMRI scanner.
Results:  Analysis showed a dose-dependent linear decrease in Blood Oxygen Level Dependent activation during task performance, primarily in hippocampus, anterior cingulate, and dorsolateral prefrontal areas, with the least activation occurring during the high dose. Behavioral analysis showed a dose-dependent linear increase in reaction time, with no effects associated with either correct hits or false alarms. In all dose conditions, driving speed decreased significantly after a VO stimulus. However, at the high dose this decrease was significantly less. Passenger-side line crossings significantly increased at the high dose.
Conclusions:  These results suggest that driving impairment during secondary task performance may be associated with alcohol-related effects on the above brain regions, which are involved with attentional processing/decision-making. Drivers with high blood alcohol concentrations may be less able to orient or detect novel or sudden stimuli during driving.     

The Relationship Between Induced Behavioural Aggression and Mood after the Consumption of Two Doses of Alcohol

Alcohol in two doses (0.75 g/kg and 0.25 g/kg) and a placebo were administered to three matched groups of subjects. A range of measures including self-ratings, body sway and breath alcohol concentration was taken before and at 30-min intervals up to 2 h after intake. At I k after the drink the subjects performed a competitive reaction time task which elicits hostility that can be measured behaviourally and on self-ratings. It was found that subjects on alcohol responded more aggressively but rated themselves as less angry compared to subjects on placebo. Alcohol had positive dose-related mood effects. Body sway and bodily symptoms were increased by the high dose and decreased by the low dose.     

Functional Imaging of Cognitive Control During Acute Alcohol Intoxication

Background: The anterior cingulate and several other prefrontal and parietal brain regions are implicated in error processing and cognitive control. The effects of different doses of alcohol on activity within these brain regions during a functional magnetic resonance imaging (fMRI) task where errors are frequently committed have not been fully explored. Methods: This study examined the impact of a placebo [breath alcohol concentration (BrAC) = 0.00%], moderate (BrAC = 0.05%), and high (BrAC = 0.10%) doses of alcohol on brain hemodynamic activity during a functional MRI (fMRI) Go/No‐Go task in 38 healthy volunteers. Results: Alcohol increased reaction time and false alarm errors in a dose‐dependent manner. fMRI analyses showed alcohol decreased activity in anterior cingulate, lateral prefrontal cortex, insula, and parietal lobe regions during false alarm responses to No‐Go stimuli. Conclusions: These findings indicate that brain regions implicated in error processing are affected by alcohol and might provide a neural basis for alcohol’s effects on behavioral performance.     

Impulsivity, Sensation Seeking, and Behavioral and Emotional Responses to Alcohol

Three hundred forty-two male and female subjects from the Colorado Alcohol Research on Twins and Adoptees returned a mailed questionnaire that included the Eysenck Impulsivity-Venturesomeness-Empathy scales. These subjects had previously been tested in a procedure in which they were given a 0.8 g/kg dose of ethanol to bring their peak blood alcohol concentration (BAC) to near 0.10 g/dl, given topping doses to maintain this BAC over a 3-hr period, and repeatedly tested on a battery of diverse physiological, psychomotor, perceptual speed, and mood measures. Impulsivity was significantly correlated with higher levels of self-reported alcohol use and the occurrence of alcohol use problems in males, while both impulsivity and venturesomeness (sensation seeking) were significantly correlated with lessened motor impairment following alcohol use in males. These personality measures, however, were not significantly correlated with mood measures following initial alcohol dosing. Impulsivity and venturesomeness were uncorrelated with alcohol use and responses to alcohol in females, but as with males, impulsivity was related to the occurrence of alcohol use problems in females.     

Effect of low and moderate doses of alcohol on driving hazard perception latency and driving speed

Both driving speed and speed of detection of potentially hazardous events while driving have been found to correlate positively with accident rates across individuals. Alcohol ingestion is also known to increase risk of a traffic accident. This paper reports two double-blind, placebo-controlled studies: one on the effect of alcohol on driving speed and the other on the effect of alcohol on time taken to detect potential traffic hazards. Moderate drinkers aged between 30 and 55 took part. Each subject underwent three experimental conditions on separate days: no alcohol, low alcohol (0.025% BAC) and moderate alcohol (0.05% BAC). The order of conditions was counterbalanced. The moderate alcohol dose increased mean time taken to respond to hazards (2.5 s in no alcohol condition compared with 3.2 s in moderate alcohol condition) but did not affect mean driving speed (indexed by time taken to travel sections of a fixed route; 19.3 s in no alcohol compared with 19.0 s in moderate alcohol). The results support the view that at least part of the excess risk of accident associated with alcohol ingestion is attributable to an increase in the time taken to respond to traffic hazards.     

Significant Increase of Blood Alcohol by Cimetidine after Repetitive Drinking of Small Alcohol Doses

To assess effects of repetitive alcohol drinking and pre-existing first-pass metabolism on the cimetidine induced increase in blood alcohol concentrations, 20 healthy men (aged 20 to 40) of varied ethnicity and consuming less than 60 g alcohol per week underwent baseline quantitation of first-pass metabolism of alcohol. This was followed by oral administration of 0.6 g/kg ethanol given postprandially in 3 to 4 drinks spread over 135 min, before and after cimetidine (400 mg twice a day for 7 days). Blood alcohol concentrations were determined by breath analysis. First-pass metabolism was quantified by applying Michaelis-Menten kinetics to blood alcohol curves after intravenous or oral administration of equal alcohol doses. At baseline, 15 subjects had a substantial first-pass metabolism (over one sixth of the dose); their alcohol levels increased with repeated doses with a mean peak of 27 ± 3 mg/dl before and 39 ± 5 after cimetidine ( P < 0.01), an effect much greater and longer than after a single alcohol dose. Three subjects exceeded 50 mg/dl, the legal limit for driving in several countries. By contrast, in the five subjects with minimal first-pass metabolism, cimetidine did not increase alcohol levels. Thus, under conditions mimicking social drinking, cimetidine increased blood alcohol to concentrations known to impair psychomotor skills and they persisted at those levels over prolonged periods of time. In a minority of subjects, no such interaction was found, but their first-pass metabolism at baseline was absent or minimal and thus no inhibition by the drug was to be expected.     

Peril, chance, adventure: concepts of risk, alcohol use and risky behavior in young adults

This paper discusses issues in applying concepts of "risk" to alcohol use. There is a wide variety of definitions of "risk," including dimensions of positive vs. negative aspects of risk-taking, short-term vs. long-term harm, generality vs. specificity of risk behaviors, knowledge of probability of harm, and objective vs. subjective risk. Alcohol can play a role in risky behavior on multiple levels. The paper describes the methods used to examine a link between alcohol and risk-taking (population-based, person-based, event-based and experimental methods) and illustrates these methods from research findings on the association of alcohol to risky driving, crime and violent behavior, and sexual risk-taking. Theoretical models of the association of alcohol and risk-taking are outlined, and the implications of these models for alcohol policy and prevention are discussed.     

Interaction between Marihuana and Ethanol: Effects on Psychomotor Performance

This is a report of the results of a placebo-controlled study in which the effects of the interaction between ethanol and marihuana on drug plasma concentrations, subjective ratings of intoxication, heart rate acceleration, and psychomotor performance were investigated. Six healthy, male, paid volunteers, moderate users of ethanol and marihuana, participated in the study. Ethanol (0.42 g/kg, 0.85 g/kg, or placebo) was administered over a 30-min interval. Fifteen minutes later the subjects smoked, in their customary manner, NIDA cigarettes containing 2.4% or 0.0004% (placebo) delta-9-tetrahydrocannabinol (THC). Each subject was tested in a single-blind, latin-square crossover design with the following six conditions: placebo ethanol/placebo marihuana; low dose ethanol/placebo marihuana; high dose ethanol/placebo marihuana; placebo ethanol/marihuana; low dose ethanol/marihuana; and high dose ethanol/marihuana. The variables measured in the study were: (a) subjective rating of ethanol and/or marihuana intoxication; (b) heart rate; (c) accuracy and latency of response in the Simulator Evaluation of Drug Impairment (SEDI) task; (d) blood ethanol concentration by gas chromatography; and (e) plasma concentration of THC by radioimmunoassay. The results indicate that the decrements due to ethanol in performance of skills necessary to drive an automobile were significantly enhanced by marihuana in an additive and perhaps synergistic manner. The administration of ethanol prior to marihuana smoking did not produce significant effects on the subjective rating of "high," heart rate acceleration, or THC plasma concentration.     

Opioidergic modulation of ethanol self-administration in the ventral pallidum

Background: Striatopallidal medium spiny neurons have been viewed as a final common path for drug reward and the ventral pallidum as an essential convergent point for hedonic and motivational signaling in the brain. The medium spiny neurons are GABAergic, but they colocalize enkephalin. Purpose of this study was to investigate the role of the opioidergic mechanisms of the ventral pallidum in ethanol self‐administration behavior. Methods: Effects of bilateral microinjections of μ‐, δ‐, and κ‐opioid receptor agonists and antagonists into the ventral pallidum on voluntary ethanol consumption were monitored in alcohol‐preferring Alko Alcohol (AA) rats using the 90‐minute limited access paradigm. Results: Stimulation of μ‐opioid receptors with DAMGO (0.01 to 0.1 μg) or morphine (1 to 10 μg) in the ventral pallidum decreased ethanol intake dose‐dependently. Conversely, blocking μ‐receptors with CTOP (0.3 to 3 μg) increased ethanol intake significantly. Unlike CTOP, DAMGO also increased locomotor activity. Consumption of ethanol was not modified significantly by a broad‐spectrum opioid receptor antagonist naltrexone, by δ‐opioid receptor agonist DPDPE or antagonist naltrindole, or by a κ‐opioid receptor agonist U50,488H or antagonist nor‐BNI. Conclusions: The study provides evidence for μ‐ but not δ‐ or κ‐opioid receptors in the ventral pallidum playing a role in the regulation of voluntary ethanol consumption. Furthermore, present findings give support to earlier work, suggesting an essential role of pallidal opioidergic transmission in drug reward.     

Administration of memantine during ethanol withdrawal in neonatal rats: effects on long-term ethanol-induced motor incoordination and cerebellar Purkinje cell loss

Background: Alcohol consumption during pregnancy can damage the developing fetus, illustrated by central nervous system dysfunction and deficits in motor and cognitive abilities. Binge drinking has been associated with an increased risk of fetal alcohol spectrum disorders, likely due to increased episodes of ethanol withdrawal. We hypothesized that overactivity of the N‐methyl‐D‐aspartate (NMDA) receptor during ethanol withdrawal leads to excitotoxic cell death in the developing brain. Consistent with this, administration of NMDA receptor antagonists (e.g., MK‐801) during withdrawal can attenuate ethanol’s teratogenic effects. The aim of this study was to determine whether administration of memantine, an NMDA receptor antagonist, during ethanol withdrawal could effectively attenuate ethanol‐related deficits, without the adverse side effects associated with other NMDA receptor antagonists. Methods: Sprague–Dawley pups were exposed to 6.0 g/kg ethanol or isocaloric maltose solution via intubation on postnatal day 6, a period of brain development equivalent to a portion of the 3rd trimester. Twenty‐four and 36 hours after ethanol, subjects were injected with 0, 10, or 15 mg/kg memantine, totaling doses of 0, 20, or 30 mg/kg. Motor coordination was tested on a parallel bar task and the total number of cerebellar Purkinje cells was estimated using unbiased stereology. Results: Alcohol exposure induced significant parallel bar motor incoordination and reduced Purkinje cell number. Memantine administration significantly attenuated both ethanol‐associated motor deficits and cerebellar cell loss in a dose‐dependent manner. Conclusions: Memantine was neuroprotective when administered during ethanol withdrawal. These data provide further support that ethanol withdrawal contributes to fetal alcohol spectrum disorders.     

Alcohol levels are increased in social drinkers receiving ranitidine

OBJECTIVE: Ranitidine increases blood alcohol concentrations by decreasing the first pass metabolism of ethanol. The effect of ranitidine on alcohol levels has been found to be variable when using large doses of alcohol or conditions in which its first pass metabolism is known to be minimal. Despite a consensus that the drug increases alcohol levels after small doses of ethanol, this effect has been considered inconsequential, because of the low alcohol levels. However, social drinking comprises repetitive consumption of small doses of alcohol and the ranitidine effect could thereby be potentiated. METHODS: To study this factor, alcohol levels were determined by breath analysis in nine men (social drinkers), after four drinks of 0.15 g/kg ethanol given postprandially every 45 min, before and after ranitidine (150 mg b.i.d. for 7 days). RESULTS: Their blood alcohol increased with repeated doses, reaching peak values of 24+/-3 mg/dl before ranitidine and 33+/-2 after ranitidine (p = 0.04). In seven of the nine subjects blood alcohol exceeded 25 mg/dl, a level at which impairment of judgment and of finely tuned skills occurs and which exceeds legal limits of driving in some European countries. Moreover, the high levels persisted for a longer time with than without the drug. These effects were associated with a 62% decrease in first pass metabolism. CONCLUSION: Under conditions mimicking social drinking, ranitidine increases blood alcohol to levels known to impair psychomotor skills needed for driving.     

Alcohol Reactions in Subjects of European Descent: Effects on Alcohol Use and on Physical and Psychomotor Responses to Alcohol

Self-reports of reactions to small amounts of alcohol, obtained between 1990 and 1992, were compared with reports of alcohol use, obtained in 1990–1992 and also in 1979–1981, in twin subjects of European descent. Data on subjective, physiological, psychomotor, and metabolic responses to a test dose of alcohol, taken in 1979–1981, were also available. Alcohol reactions were more common in women than in men, and were associated with less alcohol use, both at the time that information about reactions was obtained and as recorded on average 12 years previously, in both sexes. Physiological and psychomotor responses to alcohol were similar across the reaction groups, except that deterioration in standing steadiness was greater in those who subsequently reported adverse reactions to alcohol. Contrary to expectation, skin temperature changes after alcohol were less in the subjects who reported always reacting to alcohol than in the other groups. Subjective reports of intoxication were greatest in subjects who subsequently reported alcohol reactions. The pattern of twin pair concordance for reactions suggests low heritability, so alcohol reactions in subjects of European descent are not caused by a single gene of high penetrance of the type found in the Asian alcohol flush reaction.     

Alcohol effects during acamprosate treatment: a dose-response study in humans

BACKGROUND: Acamprosate (calcium acetyl homotaurinate) reduces alcohol intake in animals and increases abstinence rates in alcohol-dependent persons. Acamprosate's mechanism of action, however, remains poorly understood. In order to examine whether acamprosate/alcohol interactions contribute to acamprosate's efficacy, the present double-blind, placebo-controlled human laboratory study examined effects of acamprosate on the pharmacokinetics and subjective, psychomotor, and physiological effects of alcohol in heavy drinkers. METHODS: In a six-week within-subject design, participants were maintained on acamprosate (0, 2, and 4 g, p.o., double-blind, in counterbalanced order) for 11 days at each dose. Physiological, subjective, and psychomotor measures were collected daily during each dosing cycle. During each acamprosate dose condition, subjects were challenged with 0, 0.5, and 1.0 g/kg ethanol (p.o., counterbalanced order) during three separate laboratory sessions. Subjective, physiological, and psychomotor effects of alcohol, and breath alcohol levels were collected at baseline and at 30-min intervals for a 3-hr post-administration period. RESULTS: Acamprosate alone did not substantially affect subjective, physiological, or psychomotor performance measures. Acamprosate did not alter alcohol pharmacokinetics, or alcohol-induced behavioral impairment or tachycardia, and most subjective alcohol effects were also unaltered by acamprosate as well. Although a trend appeared for acamprosate to increase subjective ratings of intoxication following the lower (0.5 g/kg) alcohol dose, adjustment for individual differences in blood alcohol level eliminated this effect, suggesting the trend was not due to a central effect of acamprosate. CONCLUSIONS: Acamprosate does not alter alcohol pharmacokinetics, acute physiological or psychomotor alcohol effects, or most subjective alcohol effects.     

Behavioral Effects and Pharmacokinetics of Low-Dose Intravenous Alcohol in Humans

Alcohol has physiological effects on the human central nervous system at blood alcohol concentrations (BACs) as low as 9 mg/dl. It is unknown, however, if humans can perceive the effects of such low doses of alcohol. Furthermore, low BACs can be difficult to measure. The purpose of this experiment was to: (1) assess the ability of humans to perceive subjective effects of low BACs; (2) measure behavioral effects of low BACs on a psychomotor performance task; and (3) test the sensitivity and accuracy of the transdermal alcohol sensor (TAS) for measuring low BACs from skin. Five men and seven women were administered single-blind intravenous infusions of ethyl alcohol in 5% dextrose/water to achieve peak BACs of 0,10,20, and 40 mg/dl. Subjective intoxication scales and a computer administered continuous performance task (CPT) were used to assess alcohol effects. BACs were estimated from skin, blood, and breath. The only alcohol-induced sensation significantly increased during the alcohol infusions was anesthesia measured by the Alcohol Sensation Scale on the descending limb of the BAC curve. The subjective positive-reinforcing stimulant and mood effects of alcohol were not reported until subjects were administered the 40 mg/dl alcohol infusion. Other measures of subjective intoxication and sedation, and the CPT were unaffected by the alcohol infusions. The TAS provided a noninvasive method for estimating BACs that was comparable with estimates obtained from blood and breath, although delayed in time.     

Comparison of the effects of sleep deprivation, alcohol and obstructive sleep apnoea (OSA) on simulated steering performance.

Patients with obstructive sleep apnoea (OSA) are reported to have an increased risk of road traffic accidents. This study examines the nature of the impairment during simulated steering in patients with OSA, compared to normal subjects following either sleep deprivation or alcohol ingestion. Twenty-six patients with OSA and 12 normal subjects, either deprived of one night's sleep or following alcohol ingestion [mean (SD) alcohol blood level 71.6 mg dl(-1) (19.6)], performed a simulated steering task for a total of 90 min. Performance was measured using the tendency to wander (SD), deterioration across the task, number of 'off-road' events and the reaction time to peripheral events. Control data for OSA, sleep deprivation and alcohol were obtained following treatment with nasal continuous positive airway pressure (nCPAP), after a normal night of sleep, and following no alcohol, respectively. Patients with untreated OSA, and sleep-deprived or alcohol-intoxicated normal subjects performed significantly less well, compared to their respective controls (P<0.01 for all tests), with untreated OSA lying between that of alcohol intoxication and sleep deprivation. Alcohol impaired steering error equally throughout the whole drive, whilst sleep deprivation caused progressive deterioration through the drive, but not initially. Untreated OSA was more like sleep deprivation than alcohol, although there was a wide spread of data. This suggests that the driving impairment in patients with OSA is more compatible with sleep deprivation or fragmentation as the cause, rather than abnormal cognitive or motor skills.     

A physiologically-based pharmacokinetic (PBPK) model for alcohol facilitates rapid BrAC clamping

Alcohol clamping is a technique that maintains a constant breath alcohol concentration (BrAC) for prolonged intervals, thereby reducing experimental variance in the time course of organ exposure to alcohol, when compared with oral alcohol administration paradigms. The technique employs an intravenous (i.v.) infusion of an ethanol solution at a rate that is intermittently adjusted based on real-time BrAC measurements. In earlier studies, when the clamped state was induced with an oral ethanol loading dose, the vagaries of gastric emptying and absorption were associated with a 45 min delay (RST: reliable start time) before collection of dependent measurements could be planned with confidence. The objective of the present study was to develop an induction method that provides an earlier RST, and to compare the performance of the two methods. The "quick-clamping" method replaced the oral loading dose with a preprogrammed infusion rate profile. A three-compartment physiologically-based pharmacokinetic (PBPK) model for ethanol was constructed, then tailored to each subject using individualized estimates of model parameters. The model was used to compute the infusion-rate profile that would produce the desired time course of BrAC when infused in the corresponding subject. The two clamping methods were compared in a two-session crossover study in 20 healthy young subjects (10 males, 10 females). Compared with the oral/i.v. method, quick clamping produced a comparable precision in the control of BrACs during the clamped interval, and provided a much earlier RST (mean +/- SE for quick-clamp: 17 +/- 4 min; for oral/i.v. clamp: 45 +/- 7 min). The quick-clamping method enables, for the first time, the examination of the early-phase neuroadaptive responses to alcohol in human subjects.     

MK-801 can exacerbate or attenuate behavioral alterations associated with neonatal alcohol exposure in the rat, depending on the timing of administration

BACKGROUND: We have reported that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal in the developing rat attenuates ethanol's adverse effects on behavioral development. In the present study, we altered the timing of MK-801 delivery in relation to the last alcohol dose to determine if its protective effects were specific to the ethanol withdrawal phase. METHODS: Five groups of rats were artificially reared and exposed to alcohol in a binge-like manner on postnatal day (PD) 6, producing peak blood alcohol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups received MK-801 at various times after alcohol treatment (0, 9, 21, or 33 hr post-ethanol). The fifth alcohol-treated group received saline. Two artificially reared control groups were included: one was injected with saline and the other injected with 0.5 mg/kg MK-801. Finally, a normally reared suckle control group was also included. Activity level and performance on a spatial discrimination reversal-learning task were evaluated at PD 18 and PD 40, respectively. RESULTS: Administration of MK-801 at the same time as ethanol treatment (0 hr) produced a high rate of mortality. Ethanol exposure on PD6 increased activity level relative to controls. Administration of MK-801 at 0 hr exacerbated this ethanol-induced overactivity, whereas administration of MK-801 at 21 and 33 hr reduced the severity of ethanol-related overactivity. Similarly, ethanol exposure on PD 6 significantly increased the number of errors committed on a spatial discrimination reversal-learning task. MK-801 injections 9 hrs after ethanol exacerbated this effect, whereas MK-801 treatment 33 hrs after ethanol attenuated this effect. Thus, MK-801 administration at the time of ethanol treatment was highly toxic, whereas during the withdrawal period it was protective. CONCLUSION: These data are consistent with the hypothesis that ethanol exposure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during withdrawal. Both the acute inhibitory effects of ethanol and the excitatory effects of withdrawal may contribute to fetal alcohol effects.