Single Administration Of Ethanol Research Articles

The effects of ethanol on striatal dopamine and frontal cortical D-[3H]aspartate efflux oscillate with repeated treatment: Relevance to individual differences in drug responsiveness

Numerous inconsistencies in the reported effects of drugs that can be found in both the human clinical and animal experimental literatures have prompted attempts to identify the basis of this variability. Our data suggest that one source may derive from the tendency of many systems to oscillate in their response to repeated drug or stress exposure. In the first experiment a single administration of ethanol to male rats, either 2 or 30 minutes or 2 weeks before sacrifice suppressed amphetamine-induced dopamine efflux from striatal slices. However, when ethanol was given both 2 weeks and 30 minutes before sacrifice, the two treatments significantly attenuate each other's effects. In Experiment 2, the stress of a novel environment (black box) 30 minutes before sacrifice decreased fractional D-[3H]aspartate efflux from the medial frontal cortex. When a single injection of ethanol 1 week earlier was added to black box exposure, it depressed efflux still further. However, adding a third treatment (ethanol at 2 weeks and 1 week + black box at 30 minutes) significantly reversed the effects of the two treatments (ethanol + black box). When a four-treatment chain was used (ethanol at 3, 2, and 1 week + black box at 30 minutes), the attenuation of efflux was reinstated. These data complement other findings from this laboratory showing that repeated stress or drug exposure can lead to an oscillatory pattern of change in the effects of future exposures and, in this way, contribute to variability in drug responsiveness.

A single administration of ethanol simultaneously increases c- fos mRNA and reduces c- jun mRNA in the hypothalamus and hippocampus

We have previously demonstrated that a single administration of ethanol induces the expression of c- fos mRNA in the hypothalamic paraventricular nucleus (PVN). However, Fos protein must interact with a member of the Jun family to form functional heterodimers. To determine whether ethanol may have differential effects on c- fos and c- jun expression, we injected male rats acclimated to a 25°C environment with thanol (3 g/kg b.wt.) or saline. Using in situ hybridization histochemistry with oligonucleotide probes, we found that ethanol increased c- fos mRNA in the PVN, but decreased c- jun mRNA both in the PVN and in hippocampus. Considering that ethanol produces hypothermia and that the PVN contains neurons activated during hypothermia, we evaluated the effect of cold on c- fos and c- jun mRNA. Both cold and ethanol increased c- fos mRNA, and the effects were additive. However, c- jun mRNA levels in both PVN and hippocampus were unaffected by temperature. Finally, c- jun mRNA levels in the hippocampus were significantly reduced by chronic ethanol exposure, and this trend was also observed in the PVN. These findings demonstrate that a single injection of ethanol has opposite effects on the expression of nuclear transcription factors which interact to regulate gene expression in the nervous system.

Effects of a Single Large Dose of Ethanol on Tissue Ascorbic Acid, Drug-Metabolizing Enzymes in the Liver, and Serum and Liver Lipids in Rats Fed with a PCB-containing Diet.

The effects of a single administration of ethanol after feeding a PCB-containing diet on tissue ascorbic acid, drug-metabolizing enzymes in the liver, and serum and liver lipids of rats were investigated. Male Donryu and Wistar rats that had been fed on a 20% casein diet with or without 0.03% PCB were given a 5g/kg of body weight ethanol solution (25%, w/v) via a stomach tube, and then killed 16h after the intubation. Intake of the PCB-containing diet accelerated the disappearance of blood ethanol. Dietary PCB and a single dose of ethanol independently affected the tissue levels of ascorbic acid. The combined effect on hepatic aniline hydroxylase activity was additive or synergistic. A single dose of ethanol did not significantly affect the hepatic aminopyrine N-demethylase activity. In Donryu rats, the effects from feeding on a PCB-containing diet and those from a single dose of ethanol on serum lipids were almost additive. In Wistar rats, the effects of ethanol alone on lipids were not necessarily apparent, but the effects of ethanol after feeding with the PCB-containing diet were strongly enhanced. Ethanol alone hardly affected the liver lipids. Most lipids that were increased by PCB alone were significantly decreased or tended to be decreased by a single dose of ethanol. The serum levels of GOT and GPT were markedly increased by a single large dose of ethanol concomitant with the PCB-containing diet in both strains of rats; however, PCB alone or ethanol alone hardly changed the serum levels of GOT and GPT. These results indicate that the effects of a single large dose of ethanol on drug and lipid metabolism, and on the liver function were markedly modified by the intake of a PCB-containing diet.

Repeated ethanol administration decreases prodynorphin biosynthesis in the rat hippocampus

The effect of single and repeated (19 days) intragastric ethanol administration on prodynorphin mRNA and α-neoendorphin levels in the hippocampus of the rat was studied using in situ hybridization and RIA methods, respectively. Single ethanol administration had no effect on either of these two parameters. Repeated ethanol administration decreased both immunoreactive (ir-) α-neoendorphin (by ca. 37%) and prodynorphin mRNA (by ca. 57%) levels. Two days after the last dose of ethanol no changes in the ir-α-neoendorphin tissue content were found, whereas the level of prodynorphin mRNA remained decreased (by ca. 44%). These results suggest that repeated ethanol evokes a long-lasting decrease in the biosynthesis of hippocampal prodynorphin, this effect that may play some role in the ethanol-induced deficiency of neuronal functions.

Effects of single ethanol administration on hepatic ornithine decarboxylase induction and polyamine metabolism

The effects of a single ethanol administration on ornithine decarboxylase induction, polyamine metabolism and DNA synthesis in rat liver after partial hepatectomy were studied. Ethanol given 1 hr before partial hepatectomy at the dose of 2, 3 or 5 gm/kg body wt inhibited the increase in ornithine decarboxylase activity and that in the putrescine level in the liver 4 hr after partial hepatectomy. The hepatectomy increased the amount of ornithine decarboxylase messenger RNA expressed, and this amount was unaffected by ethanol administration. Further, ethanol did not accelerate the degradation of ornithine decarboxylase 4 hr after partial hepatectomy, indicating that the inhibition of ornithine decarboxylase activity caused by ethanol was not caused by a decrease in the ornithine decarboxylase messenger RNA level or by the acceleration of ODC degradation. The single dose of ethanol inhibited [3H]thymidine incorporation into the hepatic DNA 24 hr after partial hepatectomy. The suppression of [3H]thymidine incorporation was partially reversed by the administration of putrescine. These results suggested that ethanol inhibits the increase in ornithine decarboxylase activity after transcription, suppressing the accumulation of putrescine, which prevents DNA synthesis in response to hepatectomy.

Effects of single ethanol administration on hepatic ornithine decarboxylase induction and polyamine metabolism

The effects of a single ethanol administration on ornithine decarboxylase induction, polyamine metabolism and DNA synthesis in rat liver after partial hepatectomy were studied. Ethanol given 1 hr before partial hepatectomy at the dose of 2, 3 or 5 gm/kg body wt inhibited the increase in ornithine decarboxylase activity and that in the putrescine level in the liver 4 hr after partial hepatectomy. The hepatectomy increased the amount of ornithine decarboxylase messenger RNA expressed, and this amount was unaffected by ethanol administration. Further, ethanol did not accelerate the degradation of ornithine decarboxylase 4 hr after partial hepatectomy, indicating that the inhibition of ornithine decarboxylase activity caused by ethanol was not caused by a decrease in the ornithine decarboxylase messenger RNA level or by the acceleration of ODC degradation. The single dose of ethanol inhibited [3H]thymidine incorporation into the hepatic DNA 24 hr after partial hepatectomy. The suppression of [3H]thymidine incorporation was partially reversed by the administration of putrescine. These results suggested that ethanol inhibits the increase in ornithine decarboxylase activity after transcription, suppressing the accumulation of putrescine, which prevents DNA synthesis in response to hepatectomy.

Transition of Rat Pancreatic Juice Edema into Acute Pancreatitis by Single Ethanol Administration

The present study was done to determine the influence of single oral, intravenous and intraperitoneal ethanol administration at pre-existing pancreatic juice edema on frequency and severity of acute pancreatitis (AP). The rats were divided into six control (isolated treatment) and five study groups (edema plus varied ethanol application). 24 h postoperatively quality and quantity of macroscopic and histopathologic changes were graded on an arbitrary scale. While in the controls AP was not induced in any rat, in the study groups extrapancreatic fat necrosis and histologic lesions of the pancreas were found in the majority of animals. The individual rats revealed a remarkable variation of the severity of changes. A detailed differentiation of pancreatic necroses revealed a dominance of intrapancreatic fat necrosis and acinar necrosis at the periphery of lobules. The findings observed were widely independent of the way of ethanol administration. The present approach offers a simple and reproducible animal model to study the influence of acute ethanol application on development of AP and hints on the involvement of disturbances of the pancreatic microcirculation and of acinar cell metabolism in the pathogenesis of ethanol-induced acute pancreatitis.

Development of acute pancreatitis in rats after single ethanol administration and induction of a pancreatic juice edema

The effect of an acute gastral ethanol application and an additional induction of a pancreatic juice edema by an obstruction/hyperstimulation mechanism was studied in rats. Neither ethanol administration nor the combination of ductal obstruction and secretory stimulation resulted in an acute pancreatitis when applied independently. A combination of these factors, however, led to the development of AP in two-thirds of the rats treated in this manner. Its severity was evaluated by the degree of extrapancreatic fat necrosis, the increase in serum amylase and lipase activities, and by histologic investigations. It is assumed that a pancreatic juice edema, provoked by pancreatic secretion at temporary ductal obstruction, could be an important cofactor in formation of ethanol-induced acute pancreatitis.

The effect of single and repeated ethanol administration on hypothalamic opioid systems activity — an in vitro release study

The effect of ethanol administration on the in vitro release of α-neoendorphin (ANEO) and Met-enkephalin-Arg 6-Gly 7-Leu 8 (MEAGL), peptides derived from prodynorphin and proenkephalin, respectively, was studied in the rat hypothalamus. Single ethanol administration had no effect on the tissue level and potassium-stimulated release of these peptides. Repeated ethanol administration increased the release of ANEO and reduced the release of MEAGL from hypothalamic slices. Two days after cessation of ethanol administration the release of MEAGL returned to control values, whereas the release of ANEO was significantly inhibited. On the other hand, the tissue level of those peptides remained unchanged after repeated ethanol or 2 days after its last administration. The present study shows that repeated treatment with ethanol may lead to an increase in the prodynorphin neurons' sensitivity to the depolarizing effect of potassium. In contrast, the sensitivity of the proenkephalin system to ethanol seems to be inhibited. Thus, ethanol appears to have an opposite effect on the sensitivity of hypothalamic proenkephalin and prodynorphin neurons.

Effect of acute and chronic ethanol administration on rat liver alpha 2,6-sialyltransferase activity responsible for sialylation of serum transferrin.

The effect of a single administration and a 6-week treatment with ethanol on rat liver sialyltransferase activity towards asialoglycoproteins and N-acetyllactosamine (Gal beta 1,4GlcNAc) was studied. Since only the alpha 2,6-sialyltransferase is involved in the in vivo sialylation of transferrin, Gal beta 1,4GlcNAc was chosen as an acceptor and alpha 2,6-sialyl-N-acetyllactosamine was separated from the corresponding alpha 2,3-sialyl isomer present in the sialyltransferase reaction mixture by high-performance liquid chromatography. After a single ethanol administration there was a low (about 20%) but significant (p less than 0.005) reduction of sialyltransferase activity towards asialotransferrin as well as a reduced alpha 2,6-sialyltransferase activity towards N-acetyllactosamine. An opposite result was found in the chronically ethanol-treated rats: in these animals either the total or alpha 2,6-sialyltransferase activity was slightly higher than in control animals. Blood ethanol concentration was significantly high (3.3 +/- 1.2 mg/ml) only in the acute-treated animals, suggesting that the accumulation in the body of ethanol and/or its metabolites induces a reduction of liver alpha 2,6-sialyltransferase activity responsible for the transferrin sialylation. Current results are consistent with the finding (Stibler H, Hultcrantz R: Alcohol Clin Exp Res 11:468-473, 1987) that an enhanced level of hyposialylated transferrin isoforms is a marker of present but not previous alcohol abuse.

Formula omitted][formula omitted]electrochemical determination of extracellular dopamine in the caudate of freely-moving rats after a low dose of ethanol

Low doses of ethanol (i.e. < 1 g/kg) elicit behavioral stimulation, control discriminative performance and mediate reinforcement in rats. These effects are thought to be mediated through central dopaminergic neuronal systems. In the present study, dopamine and serotonin/ uric acid release from caudate was measured by in vivo voltammetry in freely-moving, unanesthetized rats after administration of a low dose of ethanol (600 mg/kg, IP). Within 15 min after a single ethanol administration, extracellular dopamine levels significantly increased in caudate, peaking at 35 min, and returning to baseline by 75 min. In addition, ethanol caused an attenuation of a second voltammetric signal that correlates with extracellular serotonln/uric acid concentrations, and this effect persisted through the course of the experiments. These neurochemical changes may underlie behavioral responses found after low doses of ethanol.

Ocular changes in the mouse embryo following acute maternal ethanol intoxication

The development of the eye was investigated in the mouse embryo following a single administration of ethanol plus [3H]thymidine to the dam on day 13 of gestation. After 1 hr there was no difference in the number of labelled cells/100 μm2 in the neural layer of the retina compared to controls, but there was an alcohol-related reduction in labelling density. After 24 hr there was an increase in the numbers of both pyknotic cells and mitotic figures, breaks occurred in the inner surface of the retina and cell debris was being extruded into the posterior chamber. At 48 hr the increase in pyknotic cells persisted, but there was less evidence of cell debris and the borders had been repaired. The estimated cell cycle time in the neural progenitor cells following maternal alcohol administration was increased 7-fold compared to controls. Morphometric analysis revealed that after 48 hr there were significant alcoholrelated reductions in the width and depth of the eye, in the thickness of the neural layer and in the interocular distance. It appears that many of the ophthalmic abnormalities reported in human fetal alcohol syndrome can be produced in the mouse embryo following a single episode of acute maternal intoxication during a critical period of ocular ontogeny, and that they evolve primarily from disturbances in the normal patterns of recruitment and loss of neural progenitor cells in the developing retina.

Stimulation of hepatic and renal diamine oxidase activity after acute ethanol administration

The effect of a single administration of ethanol (2 g/kg body weight) on hepatic and renal diamine oxidase activity was studied in fasted rats. Diamine oxidase activity significantly increased in liver and kidney 6 h after ethanol intubation. Pyrazole (an inhibitor of alcohol dehydrogenase), cycloheximide or actinomycin D (inhibitors of macromolecular syntheses), as well as prior adrenalectomy, prevented the ethanol-induced stimulation of diamine oxidase in the liver, but not in the kidney. The results demonstrated that the enhancement of diamine oxidase activity in the liver was due to an enzyme induction mediated by alcohol metabolism as well as by adrenals. In contrast, the stimulation of diamine oxidase activity in the kidney did not depend on synthesis of new enzyme molecules and was not mediated by ethanol metabolism or adrenal hormones.

Withdrawal-like signs induced by a single administration of ethanol in mice that differ in ethanol sensitivity.

These experiments studied changes produced by a hypnotic dose of ethanol in the LS and SS lines of mice, which differ in ethanol sensitivity. In the first experiment, animals were injected either with ethanol or saline, and activity and seizure susceptibility measured 7-9 h later when blood levels of ethanol would have reached zero. Ethanol-treated mice of both genetic lines were less active in an open field test and more susceptible to clonic convulsions induced by flurothyl than saline-injected controls. There was no difference in the magnitude of these changes in the two lines. In the control condition SS (short-sleep) mice were more active than LS (long-sleep) mice, and more susceptible than LS mice to myoclonic but not to clonic seizures. The effect of the ethanol injection on body temperature was evaluated in separate groups of animals. LS mice showed a more pronounced hypothermia than SS mice when temperature was measured 2 h after injection. Six hours after injection, SS mice exhibited a small but statistically significant overshoot in temperature, after which they again became hypothermic with respect to controls; hyperthermia was not observed in LS animals.

Damage of rat small intestine induced by ethanol

Single administration of ethanol or alcoholic beverages (5g ethanol/kg body weight) induces a decrease of the 24h excretion of fecal intestinal alkaline phosphatase (I-AP) activity of 28% (P less than 0.05) in comparison to controls (0.9% saline). Administration of higher amounts of 20% (v/v) ethanol (8g/kg body weight on 3 consecutive days) yields a decrease of fecal I-AP excretion up to 82% (P less than 0.005) in comparison to controls (saturated glucose solution). The interpretation of these results as a toxic effect of ethanol to small intestinal mucosa was supported by measurement of enzymatic activity in the small intestinal mucosa and by morphometric data.

Effects of furosemide on renal function after a single dose of ethanol.

The administration of furosemide 18 hours after a single ethanol administration demonstrated that loop of Henle sodium reabsorption was increased by ethanol.

Changes in fatty acid composition of myocardial triglyceride following a single administration of ethanol to rabbits

Even a moderate does of alcohol infused into fasted and fed rabbits (1.95 g/kg for over 2 h) induces a change in myocardial lipid metabolism. Such metabolic alterations were studied by measuring fatty acid oxidation and esterification by homogenates prepared from the hearts of these rabbits, and also by analyzing fatty acid composition of heart triglyceride. Ethanol administration resulted in depressed fatty acid oxidation and enhanced esterification. These metabolic derangements were restored towards the control value by the addition of carnitine in the incubation medium. The fatty acid analysis using gas chromatography was performed with rabbit heart triglyceride, adipose tissue, plasma FFA and rabbit food, each of them showing a slightly different composition. Ethanol was infused into either fed or fasted animals and the fatty acid composition of cardiac triglyceride was examined. There was very little difference in ethanol-induced compositional changes between the two dietary states of the animals, although in both instances the content of heart triglyceride was increased three hours after cessation of ethanol infusion. However, fatty acid composition of heart triglyceride greatly changed and showed a close resemblance to that of the plasma FFA, suggesting that the source of the increased fatty acid moiety in the myocardium is plasma FFA and that heart triglyceride undergoes turnover at a considerably high rate. However, this altered composition of cardiac triglyceride returned towards the pre-infusion pattern at a very slow pace. In particular, unsaturated fatty acid levels did not rise to the control value during a 2-week observation period, indicating that transacylation and desaturation processes in the organ, as well as re-arrangement or exchange of the acyl moiety of complex lipids among organs, are gradual.

Effects of acute and chronic ethanol administration on ribosomal protein synthesis in mouse brain and liver

The effect of ethanol on protein synthesis was studied in mouse brain and liver ribosomal preparations after acute and chronic administration of ethanol in vivo as well as after addition of ethanol in vitro . Incorporation of amino acid into protein was reduced in both brain and liver ribosomes 1.5–3 hours after a single administration of ethanol. The reduction was not temporally correlated with the elevation of blood level of ethanol and the degree of central depression. The ribosomal protein synthesis is rather insensitive to the in vitro addition of ethanol, as compared with the in vivo administration. The inhibition of protein synthesis in ribosomal preparations from acutely intoxicated animals may be due to transient alteration of either the ribosomal structure or the content of the associated messenger RNA. Chronic and continuous ingestion of ethanol (7–14 days) induces a stimulation of protein synthesis in brain and liver ribosomal systems, as well as an elevation of plasma corticosterone level.