Homosexual mounting behavior induced in male rats and rabbits by a tryptophan-free diet.

The ingestion of a diet containing all amino-acids but tryptophan causes a marked depletion of brain serotonin, tryptophan and 5-hydroxy-indoleacetic acid both in rats and rabbits. This effect persists for more than 24 hours. At the time of maximal serotonin depletion, a marked increase in male to male mounting behavior both in rats and rabbits was observed. This response was prevented by the administration of 5-hydroxytryptophan, the direct serotonin precursor. This finding supports the hypothesis that brain serotonin plays on inhibitory role in controlling male sexual behavior. Tryptophan-free diets may provide a non-pharmacological tool for studying the role of serotonin in different types of behavior.     

Effects of alprazolam on the free-choice ethanol consumption induced by isolation stress in aged rats.

Late-onset drinking is a common problem in elderly people related to stress induced by social isolation. Experiments were performed in order to evaluate the effects of alprazolam, a benzodiazepine agonist anxiolytic, on the free-choice ethanol consumption in aged rats subjected to isolation stress. The animals we offered a two-bottle choice consumption (one of 0.2% saccharin and the other with 10% ethanol/0.2% saccharin) and then exposed to 4 days of isolation stress on an irregular, unpredictable schedule. Stress resulted in significant increase in ethanol consumption. Treatment with alprazolam (1 mg/Kg) partially reversed this adverse effect of stress.     

Sucrose-enriched diet during maturation increases ethanol preference in rats

In the present study we used a diet enriched with 10% sucrose, which was consumed by adolescent animals of the experimental group for one month. We found that consumption of sweet food during sexual maturation affected alcohol preference, anxiety, and locomotor and exploratory activity in the adult rats. Our data show that easily available tasty food during adolescence probably impairs the reward system and serves as a trigger of future alcohol preference.     

Brain changes in rats induced by prenatal injection of methylazoxymethanol

Various doses (0, 1, 5, 10, 15, 20, or 25 mg/kg) of methylazoxymethanol acetate (MAM), a potent alkylating agent, were injected singly into pregnant rats intraperitoneally on day 15 of gestation. Relationships between brain weights and neurochemical changes in the cerebral hemispheres (CHs; cerebral cortex and subjacent white matter, hippocampus, amygdala) and remainder of the brain (BGDM; basal ganglia, diencephalon, and mesencephalon) were examined at 60 days of age in offspring; varying degrees of microencephaly were observed. Dose-dependent reductions in the weights of CH and BGDM were observed. Reductions in total DNA content positively correlated with decreases in brain weights also observed. Dose-dependent elevations of noradrenaline (NA) and dopamine (DA) were observed in CH at MAM levels 10 mg/kg and above; dose-dependent elevations of 5-hydroxytryptamine (5-HT) were observed at 15 mg/kg and above; and in BGDM at 20 mg/kg and above dose-dependent elevations for NA and 5-HT were observed; dose-dependent elevations at 15 mg/kg and above were observed for DA. Monoamine concentrations were negatively correlated with brain weights or total DNA contents. NA and DA concentrations increased to the extent of approximately 1.3 times of control at a time when an 18% loss of CH weight was noted in animals treated with 10 mg/kg MAM. It is suggested that the above variables might be appropriately sensitive neurochemical markers for detecting minor developmental anomalies in the brain.     

Liver necrosis induced by acute intraperitoneal ethanol administration in aged rats

It is generally agreed that the deleterious pathophysiological effects of ethanol are caused, at least partially by an increase in free radical production. However, little attention has been directed to the effects of ethanol upon elderly organisms. Male Wistar rats at ages 3, 6, 12, 18 and 24 months were treated either with a single i.p. dose of 35% ethanol (v/v) at 3 g ethanol/kg body weight or an isovolumetric amount of 0.9% saline solution. We then assessed the plasma levels of transaminases and hepatic levels of oxidative stress-related parameters, followed by liver histological evaluation. The younger rats (3 months old) were not affected by the treatment with ethanol with respect to any of the studied parameters except for a lowering of total hepatic GSH and an increase in hepatic thiobarbituric acid reactants (TBARS) formation, while animals older than 3 months were increasingly more affected by the treatment. Acute ethanol treatment elicited the similar responses to those in the 3 months-old group, plus a decrease in the hepatic and plasma levels of beta-carotene and the plasma level of alpha-tocopherol, as well as an increase in the activity of plasma transaminases. In the 12,18 and 24 months old groups, there was increasing liver necrosis. These findings suggest that liver damage induced by acute ethanol administration in elderly rats may involve a lack of antioxidants.     

Effect of antiperoxidative drugs on gastric damage induced by ethanol in rats

Lesion formation due to oral administration of absolute ethanol could be prevented by parenteral pretreatment with antiperoxidative drugs such as butylated hydroxytoluene (BHT), quercetin and quinacrine. Also effective were allopurinol and oxypurinol, inhibitors of xanthine oxidase, but not superoxide dismutase (SOD) and hydroxyl radical scavengers, such as sodium benzoate and dimethyl sulfoxide (DMSO). BHT, quercetin, quinacrine and sulfhydryl compounds such as reduced glutathione and cysteamine which offer gastroprotection in vivo against ethanol inhibited lipid peroxidation induced in vitro by ferrous ion in porcine gastric mucosal homogenate, but SOD, sodium benzoate, DMSO, allopurinol and oxypurinol did not. These results suggest the possibility that an active species, probably derived from free iron mobilized by the xanthine oxidase system, other than oxygen radicals such as hydroxyl radicals, contributes to lipid peroxidation and lesion formation in the gastric mucosa after absolute ethanol administration.     

Brain lesions induced by hypertonic saline in mice: dose and injection route and incidence of lesions

A single injection of hypertonic saline produced brain lesions with corresponding nervous signs in mice. The lesions were most often found in the hippocampus and were characterized by degeneration and loss of pyramidal cells. They could be induced effectively by a single administration of 20 ml of 25% saline/kg orally or of 30 ml of 8.5% saline/kg intraperitoneally. This simple experimental system seems to be a useful model of central nervous system involvement.     

Dissociative state in rats induced by ethanol and possibilities of the pharmacological correction of this phenomenon

It was shown that a state of dependent learning (SDL) developed in response to ethanol (1.2 g/kg) during experimental learning of rats in conditions of T-maze. Piracetam, lithium hydroxybutyrate, litonit and new oxypyridine derivative 3-OP given in combination with ethanol prevented the development of SDL and reduced an already formed SDL. The above-mentioned combinations made the learning more difficult. It is assumed that changes in the activity of dopaminergic system, as well as membranotropic and antioxidant effects of the investigated drugs play the most important role in the mechanisms of SDL reduction.     

Alterations in hepatic metabolism of sulfur-containing amino acids induced by ethanol in rats

Summary.  Alterations in hepatic metabolism of S-amino acids were monitored over one week in male rats treated with a single dose of ethanol (3 g/kg, ip). Methionine and S-adenosylhomocysteine concentrations were increased rapidly, but S-adenosylmethionine, cysteine, and glutathione (GSH) decreased following ethanol administration. Activities of methionine adenosyltransferase, cystathionine γ-lyase and cystathionine β-synthase were all inhibited. γ-Glutamylcysteine synthetase activity was increased from t = 8 hr, but GSH level did not return to control for 24 hr. Hepatic hypotaurine and taurine levels were elevated immediately, but reduced below control in 18 hr. Changes in serum and urinary taurine levels were consistent with results observed in liver. Cysteine dioxygenase activity was increased rapidly, but declined from t = 24 hr. The results show that a single dose of ethanol induces profound changes in hepatic S-amino acid metabolism, some of which persist for several days. Ethanol not only inhibits the cysteine synthesis but suppresses the cysteine availability further by enhancing its irreversible catabolism to taurine, which would play a significant role in the depletion of hepatic GSH. Received April 26, 2002 Accepted June 12, 2002 Published online October 14, 2002 Authors' address: Young C. Kim, Ph.D., Professor of Toxicology, College of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul, Korea, Fax: +82-2-872-1795, E-mail: youckim@snu.ac.kr Abbreviations: CβS, cystathionine β-synthase; CDC, cysteine sulfinate decarboxylase; CDO, cysteine dioxygenase; CγL, cystathionine γ-lyase; GCS, γ-Glutamylcysteine synthetase; GSH, glutathione; MAT, methionine adenosyltransferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine.     

Influence of a lipogenic diet on the cholesterol synthesis in rats in vivo.

An inhibition of the cholesterol synthesis by a lipogenic diet in rat liver is described. The inhibition could be shown with glucose or mevalonate as tracer substances. This inhibition is located between lanosterol and cholesterol and results in a reduction of the cholesterol synthesis to about one sixth of the control group. No indication for any other inhibiting effect was obtained by these in vivo experiments.     

Cytoprotective effects of met-enkephalin and alpha-MSH on ethanol induced gastric lesions in rats.

We used the rat model of ethanol induced gastric lesions to measure cytoprotective effects of neuropeptides met-enkephalin and alpha-melanocyte stimulating hormone (alpha-MSH). The lesions were induced with i.g. application of 1 ml 96% ethanol. The peptides were given i.p. 1 h before the ethanol. Sacrifice was made 1 h after ethanol application and hemorrhagic gastric area was assessed in mm(2). alpha-MSH and met-enkephalin exhibited significant and additive cytoprotective effects. The protective effects of alpha-MSH were significantly stronger than of met-enkephalin. Almost total absence of lesions was obtained with met-enkephalin and alpha-MSH mixture 10:1 (10 mg/kg met-enkephalin and 1 mg/kg alpha-MSH). The addition of indomethacin (5 mg/kg s.c.) almost completely abolished the effect of met-enkaphalin, while alpha-MSH mediated cytoprotection was weakened but still present. Interestingly, indomethacin also blocked almost completely the cytoprotective effects of met-enkephalin and alpha-MSH mixture. The latter result may have a practical consequence for the clinical trials in which met-enkephalin and alpha-MSH could be used in combination with non-steroidal anti-inflammatory drugs.     

Nondisjunction induced by ethanol in Drosophila melanogaster females.

The effect of ethanol on chromosomal segregation was investigated in Drosophila melanogaster females homozygous for a structurally normal X chromosome marked with the recessive mutation yellow (y/y). For chronic treatments the females were kept from eclosion in food supplemented with 10% or 15% (v/v) ethanol, mated 24 or 48 h later to wild-type males and brooded in freshly prepared ethanol food. For the acute treatments 24- or 48-h-old females were exposed for 60 min to a 75% (v/v) ethanol solution by means of soaked tissue paper placed at the bottom of regular culture vials and brooded daily after mating. The results obtained show that: (1) both treatments significantly increased the frequency of X-chromosome nondisjunction; (2) after acute treatment this effect declined in later broods; (3) the yield of malformed flies in the progeny of acutely treated females was significantly higher than control values and also declined in later broods; (4) ovary analysis showed that chronic ethanol treatments caused a cessation of egg production. The induction pattern of nondisjunction and malformed flies is interpreted as giving support to the assumption that these effects may result from a direct action of ethanol. Ethanol toxicity was assessed by exposing females of different ages to a 50% or a 75% (v/v) solution for 60 min and counting the surviving flies 24 h later. The surviving fraction decreased steeply from 1-day-old (100%) to 5-day-old females (1.8%). It is suggested that toxicity may have been due to the action of a metabolite of ethanol, probably acetaldehyde.