Relations between metabolic and nervous tolerance toward ethanol in naive and chronically intoxicated rats

Interindividual differences in blood alcohol elimination rates indicating metabolic tolerance (MT) were determined in adult male Wistar rats following the injection of ethanol via chronically implanted intra-jugular catheters. Nervous tolerance (NT) was measured using a behavioral test based on the latency of drinking in 20-hr water-deprived rats following the IV injection of a challenge dose of ethanol. Individual elimination rates varied between 0.312 and 0.570 mg/ml/hr (mean ± SE: 0.427 ± 0.006) and drinking latencies (1/NT) between 45 and 255 min (mean=125 ± 12). MT and NT determinations performed on the same animals indicated no correlation between the initial degrees of tolerance. In one experiment, MT and NT measurements were obtained prior to and following chronic IV pulsed-administration (4 days) of either ethanol or physiological saline. In comparison to controls, the ethanol-treated rats showed both a significant increase (22.7%) in MT (p<0.01) and a reduction (66.8%) in the latency (1/NT) of drinking (p<0.05). The extrapolation of BALs present at the onset of drinking indicated the concomitant increase in MT of ethanol-treated animals to be negligible in accounting for the observed increase in NT and that the latter was more likely attributable to adaptive changes in CNS sensitivity. Another experiment attempted to investigate the time course of development of MT in rats during continuous IV ethanol infusion (5–9 days). Mean daily MT values were calculated on the basis of 24-hr BAL samplings and known quantities of ethanol administered. The results indicated an initial adaptive increase in MT occurring within 48 hr and attaining rates about as high as 35% above initial values. This phase was usually followed by a rapid decrease in MT below that of initial levels and associated with elevated BALs and loss of body weight due to reduced food intake. The possible role played by the MT and NT factors in the defense mechanisms involved in preference and aversion conditioning and regulating the voluntary consumption of ethanol in the naive and chronically intoxicated animal are discussed.     

Ethanol-induced changes in the spontaneous activity of single units in the hippocampus of the awake rat: a dose-response study.

The spontaneous firing rates of single units in the dorsal hippocampus of semi-restrained rats chronically prepared with bundles of fine wire niehrome microelectrodes, were monitored during an ethanol challenge. Seven doses of a 25% weight/volume ethanol solution were administered intraperitoneally to all rats, each dose being given on a separate day with an interdose interval of at least 48 hr. Each ethanol injection was preceded by two control recording periods: (1) baseline and (2) saline injection. Sixty-one units from 27 animals were studied with 7–10 units tested at each dose. The results demonstrated that single cells in the hippocampus are sensitive to ethanol, and that this sensitivity which is reflected by a depression in firing rate is dose-dependent with larger doses producing greater degrees of depression. The simultaneously recorded EEG indicated a marked bias in frontal cortical activity towards high amplitude slow waves while the hippocampal activity showed less marked but more varied changes. These findings suggest that the hippocampus is among those structures whose activity and function are particularly sensitive to ethanol, and they demonstrate that a profile of a structure's response to ethanol can be obtained when a sample of neurons is tested at a spectrum of doses.     

Development of functional tolerance to ethanol in rhesus monkeys (Macaca mulatta)

Four rhesus monkeys were extensively trained until performance reached asymptote on a two-choice discrimination-reversal task. Doses of ethanol (3 g/kg) or placebo (aqueous lactose solutions isocaloric to 3 g/kg of ethanol) were then administered by gavage 90 min prior to testing. Following an initial decrement when ethanol was first administered, performance gradually returned on subsequent days to levels which were equivalent to those found under placebo conditions despite continued drug administration. Ethanol treatment affected accuracy of responding during both the acquisition and reversal phases of the task as well as the quantity of behavior emitted by the animals. Changes in performance levels were independent of fluctuations in blood ethanol concentrations. Functional tolerance developed within approximately 18 days as indicated by the recovery of performance on the discrimination-reversal task. Furthermore, this tolerance was retained during a 24 day period during which no ethanol was administered.     

Treatment of symptomatic simple renal cysts by percutaneous aspiration and ethanol sclerotherapy

OBJECTIVE: To report our experience with the use of 95% ethanol as sclerotherapy for symptomatic simple renal cysts. PATIENTS AND METHODS: Sixty patients with 64 symptomatic simple renal cysts were treated by ultrasonography (US)-guided percutaneous aspiration and injection of 95% ethanol (31 men and 29 women, mean age 46 years, SD 22). The main presentation was renal pain in 34 patients, renal mass in nine, hypertension in 11 and haematuria in six; 24 cysts were on the right, 32 on the left and four bilateral. Patients were evaluated after 1 month and then every 6 months by clinical assessment, US and intravenous urography. Success was defined as complete when there was total ablation of the cyst and partial when there was a recurrence of less than half the original cyst volume with the resolution of symptoms. Failure was defined as the recurrence of more than half of cyst volume and/or persistent symptoms. RESULTS: After aspiration and ethanol sclerotherapy, there was microscopic haematuria in two patients and low-grade fever (<38.3 degrees C) in two, but no major complications. During a mean (range) follow-up of 19 (14-40) months there was complete cyst ablation in 54 cysts and partial resolution in 10. Pain disappeared or was much improved in all patients. After cyst ablation hypertension was well controlled with no medication in all 11 hypertensive patients and haematuria disappeared in all six affected patients. CONCLUSIONS: Ethanol sclerotherapy for symptomatic simple renal cysts is simple, minimally invasive and highly effective. We recommend it as the first therapeutic option in these patients.     

Drunkenness,Hangover, and the Heart

Cardiac effects of ethanol ingestion (1.75 g/kg within 3 hours) were examined in 8 healthy males by echocardiography and systolic time intervals in a controlled study. Heart rate (HR) was increased by 15% (p<0.05) during intoxication when blood ethanol (mean±SD) was 33.7 ±4.1 mmol/l. Left ventricular (LV) end-diastolic dimension was simultaneously shortened by 4% (p<0.01) and LV end-systolic dimension by 3% (p<0.05). Stroke volume was reduced by 12% (p<0.05). Most subjects experienced hangover symptoms 12 hours after the beginning of ethanol intake; blood ethanol was 8.8 ± 4.0 mmol/l. At this time, HR was raised by 17% (p<0.05), ejection fraction by 7% (p<0.05), and circumferential fiber shortening velocity by 19% (p<0.01); total peripheral resistance was decreased by 17% (p<0.001). The resultant increase in cardiac output amounted to 22% (p<0.01). In short, the main effect of ethanol at modest blood concentrations was to reduce LV preload without detectably impairing myocardial performance. Hangover was characterized by vasodilation as well as intensified LV myocardial and pump performances.     

Chronic alcohol exposure reduces hippocampal neurogenesis and dendritic growth of newborn neurons

Hippocampal neurogenesis is known as the formation of new neurons from the proliferating neural progenitor cells (NPC) at the dentate gyrus. Cell proliferation, survival, differentiation and maturation are critical stages leading to the generation of healthy neurons. As all of these stages can be influenced by alcohol exposure, we studied the effects of chronic alcohol on each process by immunocytochemistry for stage-specific antigens and prelabelling newborn cells with bromodeoxyuridine (BrdU). Rats were administered alcohol liquid diet or control diet for one, two or four weeks. We found that cell proliferation was inhibited as proliferating cell nuclear antigen (PCNA) expression was reduced by approximately 50% in alcohol-treated animals at all time points. Doublecortin (DCX), a microtubule protein expressed early in differentiating neurons, was progressively decreased over the duration of exposure and significantly reduced after two and four weeks of drinking. Morphological analyses of DCX-positive cells revealed that four weeks of alcohol treatment reduced the size of the dendritic tree including the total length of apical dendrites, number of nodes and endings. Furthermore, BrdU labelling demonstrated a dramatic decrease in cell survival after four weeks of drinking, while cell death was increased by such treatment. Confocal analysis indicated that over 80% of BrdU+ cells colabelled with NeuN suggesting that alcohol reduced neurogenesis. In conclusion, chronic alcohol exposure disrupts neurogenesis by decreasing NPC proliferation, inhibiting cell survival and altering morphological maturation of newborn neurons. These data implicate impaired hippocampal neurogenesis with the cognitive and affective dysfunction associated with chronic alcoholism.     

Chronic prenatal ethanol exposure alters glucocorticoid signalling in the hippocampus of the postnatal Guinea pig

The present study tested the hypothesis that chronic prenatal ethanol exposure causes long-lasting changes in glucocorticoid signalling in postnatal offspring. Pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric-sucrose/pair-feeding or water throughout gestation, and maternal saliva cortisol concentration was determined 2 h after treatment at different stages of gestation. Electrically-stimulated release of glutamate and GABA, in the presence or absence of dexamethasone, as well as glucocorticoid and mineralocorticoid receptor mRNA expression, was determined in the hippocampus and prefrontal cortex of adult offspring of treated pregnant guinea pigs. Maternal saliva cortisol concentration increased throughout pregnancy, which was associated with increased foetal plasma and amniotic fluid cortisol concentration. Ethanol administration to pregnant guinea pigs increased maternal saliva cortisol concentration during early and mid-gestation. In late gestation, ethanol administration did not increase saliva cortisol concentration above that induced by pregnancy. Chronic prenatal ethanol exposure had no effect on stimulated glutamate or GABA release, but selectively prevented dexamethasone-mediated suppression of stimulated glutamate release, and decreased expression of mineralocorticoid, but not glucocorticoid, receptor mRNA in the hippocampus of adult offspring. These data indicate that maternal ethanol administration leads to excessively increased maternal cortisol concentration that can impact negatively the developing foetal brain, leading to persistent postnatal deficits in glucocorticoid regulation of glutamate signalling in the adult hippocampus.     

Effects of venlafaxine on ethanol withdrawal syndrome in rats

The present study was designed to investigate the effects of venlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI), on ethanol withdrawal syndrome in rats. Adult male Wistar rats (187-319 g) were used for the study. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair-fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Venlafaxine (5, 10, 20 and 40 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After the 2nd, 4th and 6th hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behaviour and wet dog shakes were recorded or rated. A second series of injections was given at the 6th hour after the first one, and rats were then tested for audiogenic seizures. Venlafaxine produced some inhibitory effects on locomotor hyperactivity, stereotypic behaviours and wet dog shakes. However, a two-way anova of the data did not indicate any significant effect. It reduced the incidence of the audiogenic seizures at the 6th hour of ethanol withdrawal. Venlafaxine (20 mg/kg) also prolonged the latency of the seizures significantly. Our results suggest that acute venlafaxine treatment has limited beneficial effects on ethanol withdrawal syndrome in rats.     

Women and alcohol susceptibility: Could differences in alcohol metabolism predispose women to alcohol-related diseases?

Summary ¶These present studies have identified some important differences between male and female subjects in ethanol pharmacokinetics. The development of alcohol misuse in female subjects clearly altered the rate of ethanol elimination as well as increasing the circulating levels of blood acetaldehyde. The identification of an increased level of acetaldehyde in subjects homogenous for ADH₃ ² genotype, may in part contribute to the higher incidence of alcohol-related damage, i.e. liver cirrhosis, associated with this ADH₃ genotype. The enhanced presystemic alcohol metabolism identified in female Caucasian controls, but not female alcohol misusers, may be an important factor in removing a significant quantity of ethanol during its first pass through the liver and thereby reduce circulating acetaldehyde concentrations.Received February 3, 2003; accepted March 11, 2003 Published online July 3, 2003     

Relevance of the developmental toxicity of ethanol in the occupational setting: a review

Numerous studies have been conducted investigating the reproductive toxicology of ethanol, the overwhelming majority concerning the adverse effects of consuming alcohol in beverages during pregnancy. Because many of the in vivo studies were designed to model alcoholism, they used comparatively high doses and assessed relatively few endpoints. Outcomes may have been affected by disturbances of metabolism at such high exposures, giving rise to secondary effects on development. The available data on ethanol from "conventional" developmental toxicity study test methods of the type used for regulatory hazard assessment of chemicals are limited. It is in this context, however, i.e. the use of ethanol as an industrial chemical rather than as a component of beverages, that this review is based. Using the usual criteria applied for the purpose of hazard assessment of industrial chemicals, it is concluded that there is no evidence that industrial exposure to ethanol is a developmental toxicity hazard. Developmental toxicity may result from drinking alcoholic beverages, the threshold level for all aspects of which has yet to be de fi ned. This is not, however, considered relevant to the low blood alcohol concentrations resulting from any conceivable inhalation or dermal exposure in the workplace or through the directed use of any consumer product containing ethanol.