Mean Peak Blood Alcohol Concentrations Research Articles

Effects of all three trimester moderate binge alcohol exposure on the foetal hippocampal formation and olfactory bulb

Objective: Pre-natal alcohol exposure results in injury to the hippocampus and olfactory bulb, but currently there is no consensus on the critical window of vulnerability. This study tested the hypothesis that pre-natal exposure to a moderate dose of alcohol during all three trimester-equivalents alters development of the hippocampal formation and olfactory bulb in an ovine model, where all brain development occurs pre-natally as it does in humans.Research design and methods: Pregnant sheep were divided into saline control and a binge drinking groups (alcohol dose 1.75 g kg−1; mean peak blood alcohol concentration 189 + 19 mg dl−1).Outcome and results: The density, volume and total cell number were not different between groups for the dentate gyrus, pyramidal cells in the CA1 and CA2/3 fields and mitral cells in the olfactory bulb.Conclusions: A moderate dose of alcohol administered in a binge pattern throughout gestation does not alter cell numbers in the hippocampus or olfactory bulb and exposure during the third trimester-equivalent is required for hippocampal injury, unless very high doses of alcohol are administered. This has important implications in establishing the sensitivity of imaging modalities such as MRI in which volumetric measures are being studied as biomarkers for pre-natal alcohol exposure.

The Effect of Ethanol on Human Brain Metabolites Longitudinally Characterized by Proton MR Spectroscopy

The effect ethanol exerts on the human brain has not yet been addressed by longitudinal magnetic resonance (MR) spectroscopic experiments. Therefore, we longitudinally characterized cerebral metabolite changes in 15 healthy individuals by proton magnetic resonance spectroscopy ((1)H-MRS) subsequent to the ingestion of a standard beverage (mean peak blood alcohol concentration (BAC): 51.43 +/- 10.27 mg/dL). Each participant was examined before, over 93.71 +/- 11.17 mins immediately after and 726.36 +/- 94.96 mins (12.11 +/ -1.58 h) past per os alcohol exposure. Fronto-mesial and cerebellar ethanol concentrations over time were similar as determined by the LCModel analysis of spectral data. Alcohol-induced changes of fronto-mesial creatine, choline, glucose, inositol and aspartate levels at 5.79 +/- 2.94 [corrected] mins upon ingestion as well as cerebellar choline and inositol levels at 8.64 +/- 2.98 [corrected] mins past exposure. Closely associated with ethanol concentrations, supratentorial creatine, choline, inositol and aspartate levels decreased after ethanol administration, whereas glucose levels increased. Similarly, infratentorial choline and inositol concentrations were negatively correlated with ethanol levels over time. There were no changes in N-acetyl-aspartate levels upon alcohol exposure. Furthermore, no influence of ethanol on brain water integrals was detected. Ethanol consumption may directly increase oxidative stress and the neuronal vulnerability to it. In addition, our results are compatible with ethanol-induced cell membrane modifications and alternative energy substrate usage upon alcohol exposure.

Maternal adrenocorticotropin, cortisol, and thyroid hormone responses to all three-trimester equivalent repeated binge alcohol exposure: ovine model

Alcohol-mediated alterations in hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid axis function are two proposed mechanisms by which alcohol causes neurodevelopmental injury to the fetus. We previously reported that third-trimester equivalent only alcohol exposure in sheep results in increases in the maternal and fetal adrenocorticotropin and cortisol levels, and decreases in the fetal thyroid hormones T 3 and T 4 and maternal T 3 levels. In this study, we wished to characterize the maternal HPA and hypothalamic-pituitary-thyroid hormone responses to repeated binge alcohol exposure during all three-trimester equivalents of pregnancy in sheep. Pregnant ewes received intravenous infusions of alcohol at doses of 0.75, 1.25, or 1.75 g/kg over 1 h with mean peak blood alcohol concentrations of 90, 126, or 183 mg/dl, respectively, on 3 consecutive days each week beginning on gestational day (GD) 4. Maternal blood samples were collected on GDs 6, 40, 90, and 132. Maternal plasma concentrations of adrenocorticotropin and cortisol increased in response to the high alcohol dose, and the magnitude of these elevations was not different across gestation. Thyroid hormone levels were not different when comparing among treatment groups at any time point during gestation. However, there was an ontogenetic decrease in the maternal T 3 concentration beginning between GDs 6 and 40 and a decrease in maternal T 4 and free T 4 beginning between GDs 40 and 90. The current findings suggest that (1) maternal alcohol consumption at any time during gestation stimulates the HPA axis, (2) maternal HPA responsiveness to alcohol does not change across gestation, (3) binge alcohol exposure at these doses lasting all three-trimester equivalent of human brain development does not reduce maternal thyroid hormone concentration, (4) alterations in fetal thyroid function in response to alcohol exposure do not occur as a result of diminished maternal thyroid hormone contribution, and (5) there is an ontogenetic decrease in ovine maternal thyroid hormones over gestation.

TIME COURSE AND REGIONAL DISTRIBUTION OF CORTICAL CHANGES DURING ACUTE ALCOHOL INGESTION

Behavioral effects of alcohol are known to be greater when the blood alcohol is rising, known as the Mellanby effect; however, research investigating the cortical changes during this period is scarce. The objective of this study was to investigate the effects of consumption of alcohol on cortical activity measured by the electroencephalogram (EEG) during the absorption or rising phase of alcohol. EEG signals were recorded using the entire 10/20 montage system. The experimental design consisted of a repeated measures randomized crossover design in which subjects acted as their own control. This involved recording two EEG baseline measures, each of which was followed by a placebo or alcohol condition, delivered over two days for ten subjects. All subjects had a 50% chance of receiving the alcohol first. All subjects were shown to have mean peak blood alcohol concentration (BAC) levels of around. 03%. No significant differences were found between the two baselines. Significant increases in EEG magnitude occurred in the theta (4-7.75 Hz), alpha 1 (8-9.75 Hz), and beta 1 (13.25-19.75 Hz) spectrum in the frontal EEG regions, and alpha 1 (8-9.75 Hz,) in the central and posterior regions. No significant changes were found in the theta (4-7.75 Hz) or beta (13.5-30 Hz) spectrums in the central and posterior regions. There were also no significant results for alpha 2 (10-13 Hz,) in any of the regions. These results suggest that rapid cortical changes occur within the first 35 min after alcohol consumption.

Selective and Enduring Deficits in Spatial Learning After Limited Neonatal Binge Alcohol Exposure in Male Rats

In rats, heavy bingelike alcohol exposure during the neonatal brain growth spurt [postnatal days (PD) 4-9] can impair development of spatial learning. This study tested whether binge exposure limited to the latter half of this period (PD 7-9) produced selective spatial learning deficits that endured into adulthood. On PD 7 to 9, Long-Evans rats were given intubations of alcohol (5.25 g/kg/day), sham intubations, or no intubations. Rats were tested as adults (>or=PD 70) in the Morris water maze under one of three different conditions: place (submerged escape platform in the same location each trial), random (submerged platform in a different, random location each trial), or redundant (visible platform that protruded above the water, in the same location for each trial). A 60-sec probe trial (with no platform present) followed the last acquisition trial. The mean peak blood alcohol concentration was 401 mg/dl on PD 7. Neonatal alcohol treatment significantly impaired acquisition and reduced place biases on the probe trial in place-trained males, but not females. Neonatal alcohol treatment had no significant effects on acquisition performance of the random or redundant groups. Redundant training yielded rapid acquisition for all groups. The visible cue overshadowed place cues for all treatment groups, but small place biases were evident in controls. After random training, no group showed place biases. Heavy alcohol exposure in rats limited to the last half of the neonatal brain growth spurt caused enduring deficits in spatial learning, but only in males. The deficits were specific to place learning in the Morris water maze and emerged only when learning and performance depended on the use of distal place cues.

Alcohol‐Induced Purkinje Cell Loss with a Single Binge Exposure in Neonatal Rats: A Stereological Study of Temporal Windows of Vulnerability

Previous research has shown that the early neonatal period of rats is one of enhanced vulnerability to cerebellar Purkinje cell loss associated with binge-like alcohol exposure, with a prominent sensitive period during the first neonatal week. In this study, an unbiased count of the total number of Purkinje cells was obtained using the stereological optical fractionator, in groups of rats given a single binge-like alcohol exposure either during the most vulnerable neonatal period [postnatal day (PD) 4] or during a later, less vulnerable period (PD 9). Using artificial rearing methods, rats were given 6.6 g/kg of alcohol either on PD 4 or on PD 9, delivered as a 15% (v/v) solution in milk formula on two consecutive feedings of the designated day. Control groups included an artificially reared gastrostomy control and a normally reared suckle control. The mean peak blood alcohol concentrations were not different between the PD 4 and PD 9 alcohol groups, averaging 374 and 347 mg/dl, respectively. The rats were perfused on PD 27. A uniform random sample of sections was obtained from serial frozen sections through the cerebellum, stained with thionin, and Purkinje cells were counted from a uniform random sample of locations on each section with the three-dimensional optical fractionator. The number of Purkinje cells in the suckle control and gastrostomy control groups did not differ from each other, averaging 3.94 (+/- 0.19) and 3.58 (+/- 0.22) x 10(5) cells, respectively. Binge exposure on PD 4 induced significant cell loss (mean of 2.05 +/- 0.20 x (10(5) Purkinje cells), whereas binge exposure on PD 9 did not induce significant Purkinje cell loss (3.70 +/- 0.39 x 10(5) Purkinje cells). These findings confirm that a single neonatal binge alcohol exposure produces pathological Purkinje cell loss, provided that it occurs during the period of enhanced vulnerability coinciding with the early stages of dendritic outgrowth.

Sex Differences in Vulnerability to Developmental Spatial Learning Deficits Induced by Limited Binge Alcohol Exposure in Neonatal Rats

The two main objectives of this study were (1) to replicate previous findings that 6 days of binge-like exposure to alcohol during the neonatal brain growth spurt induces significant place learning deficits in juvenile rats and (2) to determine whether more limited (3-day) binge-like exposure during the neonatal period induces place learning deficits and whether the effects depend on the developmental timing of the exposure. Using artificial rearing methods and a split-litter experimental design, groups of male and female neonatal rats were given binge-like exposure to 4.5 g/kg/day of ethanol in milk formula either on Postnatal Days (PD) 4–6, PD 7–9, or PD 4–9, which yielded mean peak blood alcohol concentrations of 230–260 mg/dl. Controls included an artificially reared gastro- stomy control group (GC) given an isocaloric milk formula diet on PD 4–9 and a suckle control group reared normally by lactating dams. Acquisition of place learning in the Morris spatial navigation task was trained for 6 consecutive days beginning on PD 26; a probe trial was given at the end of the sixth day. As expected, both males and females given alcohol on PD 4–9 had significant deficits in acquisition and probe trial performance relative to SC and GC groups. Males given the PD 7–9 exposure had significant place learning deficits which were as severe as with the full 6-day exposure. The PD 4–6 exposure in males produced only a nonsignificant trend toward slower acquisition. Females were not significantly affected by either 3-day exposure. The latter phase of the neonatal brain growth spurt appears to constitute a sex-specific period of enhanced vulnerability to alcohol-induced developmental spatial learning deficits.

Lipid peroxidation in rats chronically fed ethanol.

Chronic alcohol consumption induces cytochrome P450IIE1, enabling habitual abusers to consume far greater quantities of alcohol than normal subjects. This pathway of metabolism leads to the production of free radical species, which cause tissue damage through peroxidation of cell membranes. Groups of Wistar rats of equal male: female ratio (n = 24) were fed alcohol by gavage twice daily to achieve a dosage of 15 g/kg body weight. Mean peak blood alcohol concentrations of 186 mg% were produced in males and 156 mg% in females. The animals were allowed free access to standard laboratory chow and water. Control animals were pair-fed to the alcoholic group and fed isocaloric glucose by gavage. Groups of animals were killed between 9 and 11 am on consecutive mornings, after nocturnal feeding, since it has previously been shown that fasting rapidly depletes hepatic glutathione concentrations. Hepatic glutathione was measured by a spectrophotometric enzymatic recycling procedure. As a marker of lipid peroxidation hepatic malonaldehyde (MDA) was measured by high performance liquid chromatography. Hepatic MDA was increased in the alcoholic group (p < 0.001), as was total hepatic glutathione (p < 0.0001). Plasma concentrations of alpha-tocopherol were increased in the alcoholic group, but ascorbic acid and superoxide dismutase values were not affected. No sex differences were detected. The increased MDA production in the alcohol group is strong evidence that lipid peroxidation is a mechanism of alcoholic tissue damage. The rise in hepatic glutathione may be an adaptive response to free radical production that protects the rat against tissue damage.

Developing rat Purkinje cells are more vulnerable to alcohol-induced depletion during differentiation than during neurogenesis

This study compared the extent of cerebellar Purkinje cell depletion induced by administering alcohol to rats during two temporally distinct periods of Purkinje cell development-neurogenesis and early differentiation. One group received alcohol (5 g/kg/day) during and shortly after Purkinje cell neurogenesis (gestational days 13–18) via oral intubation of pregnant dams. A second group received alcohol (2.5 g/kg/day) during early Purkinje cell differentiation (postnatal days 4–9) via artificial rearing of pups. The two alcohol treatment protocols were designed to match the cyclic daily blood alcohol profiles of the two groups as closely as possible. Pair-fed intubated controls, artificially reared gastrostomy controls, and normally reared ad lib/suckle controls were also evaluated. Mean peak blood alcohol concentrations (BACs) were 266 mg/dl for the intubated pregnant dams and 205 mg/dl for the pups exposed postnatally. Purkinje cell profiles were counted from single, 2-μm-thick midsaggital sections on postnatal day 10. Alcohol exposure during neurogenesis resulted in no significant change in Purkinje cell profile densities. Exposure during differentiation produced significant reductions in Purkinje cell profile densities, predominantly in the early maturing regions of the vermis (lobules I–IV and IX–X). These results indicate that Purkinje cells are more vulnerable to alcohol-induced population depletion during differentiation than during neurogenesis.

Impairment and recovery under repeated doses of alcohol: Effects of response-outcomes

This research examined the behavioral effect of alcohol during rising and declining blood alcohol concentrations (BACs) when the dose was repeated three times (mean peak BAC = 78 mg/100 ml). A total of 36 male social drinkers learned a complex psychomotor task and subsequently performed it at intervals after alcohol was received. Subjects performed under one of two conditions: an experimental (E) treatment associated drug-compensatory (nonimpaired) task performance with a positively reinforcing outcome or a control (C) treatment associated no environmental consequence with performance. E treatment diminished impairment at all positions on the BAC curve and carried over to result in progressively less impairment when the dose was repeated. In contrast, C treatment tended to increase impairment around the BAC curve with repeated doses. The rate of recovery during declining BACs remained stable across sessions and was not altered by the treatments. The results imply that impairment under a dose of alcohol is governed by two processes: response-outcome associations that determine the amount of impairment displayed under a dose and some adaptive process that determines the rate of recovery with time during exposure to a dose.

Effect of omeprazole on gastric first-pass metabolism of ethanol.

Some commonly used H2-receptor antagonists affect gastric first-pass metabolism of ethanol and lead to unexpectedly high blood alcohol concentrations after consumption of alcohol. To investigate whether omeprazole--a substituted benzimidazole recently approved for clinical use--has a similar harmful effect, we administered a moderate dose of ethanol (0.3 g/kg body wt) orally to seven normal volunteers before and after one week of omeprazole administration (20 mg daily). No significant effect of the drug was found on either mean peak blood alcohol concentrations or on areas under the blood alcohol curve; neither did these parameters differ significantly before or after an acute dose of omeprazole (13.2 mg/kg body wt) in rats, whether ethanol (0.25 g/kg body wt) was administered intragastrically or intravenously. In vitro, omeprazole in concentrations likely to occur in the gastric lumen (0.01-1.0 mM), did not affect gastric alcohol dehydrogenase activity of humans or rats. Thus omeprazole does not affect gastric first-pass metabolism of ethanol and can be considered as a safe choice for the treatment of patients who do not refrain from alcohol consumption during therapy.

Effect of Concentration of Ingested Ethanol on Blood Alcohol Levels

The effect of the concentration of ingested ethanol on the resulting blood alcohol concentrations (BAC) was tested in both humans and rats. In humans, when 0.3 g/kg body weight ethanol was ingested postprandially, the mean area under the blood alcohol curve (AUC) and the mean peak BAC were significantly lower with a concentrated (40% w/v) than with a dilute (4%) solution. Similarly, rats in the fed state exhibited decreasing mean AUCs with increasing concentrations (4%, 16%, and 40%) of intragastrically administered ethanol (1.0 g/kg). Pharmacokinetic analysis comparing intragastric and intraperitoneal administration of ethanol to rats indicated that the more concentrated solution resulted in less alcohol reaching the systemic circulation (4%: 0.896 +/- 0.074 g/kg: 16% 0.772 +/- 0.072 g/kg; 40%: 0.453 +/- 0.037 g/kg) and suggested that this affect could be attributed to two factors: increased gastric retention of ethanol (4%: 0.109 +/- 0.024 g/kg; 16%: 0.102 +/- 0.016 g/kg; 40%: 0.214 +/- 0.042 g/kg) and a large increase in first-pass metabolism (4%; 0.004 +/- 0.054 g/kg; 16%: 0.145 +/- 0.048 g/kg; 40%: 0.329 +/- 0.044 g/kg). In contrast to the results in the fed state, in humans fasted overnight the concentration of alcohol consumed (4%, 16%, and 40%) had no significant effect on mean AUCs. In fasted rats, mean AUCs after intragastric intubation of the two lower concentrations of ethanol (4% and 16%) were comparable to those found after intraperitoneal injection, and only the highest ethanol concentration (40%) produced a lower mean AUC.(ABSTRACT TRUNCATED AT 250 WORDS)

A single day of alcohol exposure during the brain growth spurt induces brain weight restriction and cerebellar Purkinje cell loss

The period of rapid brain growth that occurs relatively late in development has been shown to be vulnerable to alcohol-induced brain growth deficits and neuron loss in rats using repeated daily exposure to alcohol. This study examined whether a condensed exposure (binge) restricted to a single day during this period would be sufficient to restrict brain growth and produce neuron depletion. Using artificial rearing, alcohol was given to neonatal rats in two consecutive feedings on postnatal day 4, using a total dose of either 6.6 g/kg or 3.3 g/kg. The higher dose produced mean peak blood alcohol concentrations of 362 mg/dl, while the lower dose produced mean peak BACs of 153 mg/dl. The higher dose significantly restricted whole brain, forebrain, cerebellum and brain stem weights on postnatal day 10, with the cerebellum being most severely reduced. Cerebellar Purkinje cells, counted from a 2-μm section from the midsagittal vermis, were significantly reduced in the 6.6 g/kg group. Purkinje cell loss relative to controls was significant in most lobules (I–V, IX and X), but, notably, was not significant in the later maturing regions (lobules VI and VII). The 3.3 g/kg group had no significant reductions in regional brain weights. Although the overall number of Purkinje cells was nonsignificantly reduced relative to controls, the 3.3 g/kg dose did produce significant loss of Purkinje cells in lobule II. Exposure to high peak BACs, even for a relatively short period during the brain growth spurt, constitutes a substantial risk to the developing brain, and even a moderate exposure may result in loss of more vulnerable neurons. The pattern of cell death produced suggests that the maturational or metabolic state of Purkinje cells at the time of the alcohol insult may influence the vulnerability of these neurons to an alcohol insult.

EFFECT OF LOW BLOOD-ALCOHOL CONCENTRATIONS IN SIMULATED DAY AND NIGHT DRIVING.

A study was carried out to determine the influence of low concentrations of alcohol in the blood upon performance in a simulated driving task, under day and night driving conditions. Sixteen male Ss were administered three orange drinks, the last two containing pure alcohol. Mean peak blood-alcohol concentrations of 0.012% and 0.068% were obtained. After each drink S was given some vision tests and then received three trials lasting 12 min. each on the simulator at daylight and night illumination, and with glare. Four Ss also served as controls. The larger dose significantly reduced tracking accuracy under all three driving conditions. The smaller dose detrimentally affected performance in the glare condition but not in the other two treatments. Visual acuity was significantly decreased for the large dose. It was suggested that the legal limit describing alcoholic influence in driving was too conservative, and that it should be reduced in night driving conditions.