Combined Administration Of Ethanol Research Articles

A pharmaco-EEG-based assessment of the interaction between ethanol and zonisamide.

Recent research suggests a potential role for a new generation of anticonvulsant drugs, including zonisamide, in the treatment of alcohol dependence. Some elements of the central mechanism of action that zonisamide has in common with ethanol, give rise to the question of whether there is an interaction between these two agents and whether there is any risk associated with the enhanced depressive effect of these agents on the central nervous system. This study uses a pharmaco-EEG method to examine the interaction of ethanol with zonisamide. The influence of zonisamide on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was determined. Zonisamide was administered p.o. as a single dose (20 or 60 mg/kg) or repeatedly at a dose of 30 mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 180 min after the administration of zonisamide. Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recording, as well as a marked decrease in the higher frequencies (13-30 and 30-45 Hz). Changes in the EEG recordings after zonisamide alone were more significant compared with these after repeated doses. In the hippocampus after single dose of drug the proportion of the low frequency (0.5-4 Hz) increased, whereas the proportion of high frequencies decreased. Combined administration of ethanol and zonisamide (60 mg/kg) resulted in a markedly synergistic effect in the examined structures. A beneficial effect of repeatedly administered zonisamide on ethanol-induced EEG changes was observed, especially in the hippocampus. Zonisamide in repeated doses decreases the sensitivity of the hippocampus to ethanol, an observation that may be important in the treatment of alcohol addiction.

Активність інтерферонзалежної 2′,5′-олігоаденілат- синтетази в лімфоїдних клітинах тимуса щурів при сумісній дії етанолу та препарату оцтовокислого цинку

The activity of interferon-induced 2',5'-oligoadenylatesynthetase (2',5'-OA-synthetase) in thymocytes of rats simultaneously treated with ethanol and acetic zinc preparation was studied. The 2',5'-OA-synthetase activity was decreased by 75% after daily ethanol administration for 14 days. The changes were less pronounced at the late terms of the experiment. In vitro stimulation of enzyme activity by inducer cycloferon was more pronounced at the late terms of ethanol action. Combined administration of ethanol and acetic zinc increased the 2',5'-OA-synthetase activity (by 81% at 21th day and by 30% at 28th day) in comparison to the group of animals that consumed ethanol only. The zinc preparation augmented the stimulation of enzyme activity induced by cycloferon, the effect was most prominent at the late terms of the ethanol action (at 28th day). Probably, ethanol depresses the synthesis of interferon or disturbs the functioning of 2',5'-oligoadenylate cascade. The acetic zinc amplifies the interferon synthesis.

Alpha1-adrenergic drugs affect the development and expression of ethanol-induced behavioral sensitization

BackgroundAccording to the incentive sensitization theory, addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems. After repeated ethanol administration, some animals develop psychomotor sensitization, a phenomenon which occurs simultaneously with the incentive sensitization. Recent evidence suggests the involvement of norepinephrine (NE) in drug addiction, with a critical role in the ethanol reinforcing properties. In this study we evaluated the influence of an agonist (phenylephrine) and an antagonist (prazosin) of alpha1-adrenergic receptors on the development and expression of behavioral sensitization to ethanol. Male Swiss mice, previously treated with ethanol or saline, were challenged with the combined administration of ethanol (or saline) with alpha1-adrenergic drugs. Prazosin (0.1; 0.5 and 1.0mg/kg) and phenylephrine (1.0 and 2.0mg/kg) administration blocked the expression of behavioral sensitization to ethanol. In another set of experiments, mice treated with 0.5mg/kg of prazosin+ethanol did not present the development of behavioral sensitization. However, when challenged with ethanol alone, they showed the same sensitized levels of locomotor activity of those presented by mice previously treated with ethanol and saline. Phenylephrine (1.0mg/kg) treatment did not affect the development of behavioral sensitization. Based on this data, we concluded that the alteration of alpha1-adrenergic receptors functioning, by the administration agonists or antagonists, affected the locomotor sensitization to the stimulant effect of ethanol, suggesting that the normal functioning of the noradrenergic system is essential to its development and expression.

The Influence of the Nitric Oxide Synthase InhibitorL-NOARG on the Effects of Ethanol in Rats after Acute Ethanol Administration

Abstract: The aim of this work was to study the effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NOARG) on the sedative and toxic effects of ethanol in rats. Ethanol at a dose of 3 g/kg, intraperitoneally induced sleep in rats (sleep time: 111.2±10.3 min.). Administration of the nitric oxide synthase inhibitor L-NOARG (20 and 40 mg/kg, intraperitoneally) 30 min. before ethanol significantly increased the duration of ethanol-induced sleep. L-NOARG at doses of 20 and 40 mg/kg reduced the exploratory activity of rats in the open-field test and significantly enhanced the sedative effect of ethanol in this test. It is possible that this effect is not caused by the interaction of ethanol with nitric oxide pathways but by synergistic CNS depression caused by ethanol and L-NOARG. L-NOARG (20 and 40 mg/kg) had no effect on ethanol concentrations in blood after acute ethanol administration (2 and 3 g/kg). Moreover, the combined administration of ethanol (2 g/kg) and L-NOARG (20 and 40 mg/kg) caused a decrease in the body weight of animals, observed for 14 days. Also, livers of these rats were studied for necrosis and connective tissue reaction. In histological studies L-NOARG at a dose of 40 mg/kg had no effect on hepatic necrosis caused by the acute administration of ethanol but strenghtened connective tissue reaction. L-NOARG is widely used in pharmacological studies, including those concerning the effects of ethanol. However, on the basis of our data the possibility of toxic interactions with ethanol should be considered.

Pharmaco-EEG-based assessment of interaction between ethanol and levetiracetam

Recent research suggests a potential role for a new generation of anticonvulsant drugs, including levetiracetam, in the treatment of alcohol dependence. Some elements of the central mechanism of action that levetiracetam has in common with ethanol, give rise to the question of whether there is an interaction between these two agents and whether there is any risk associated with the enhanced depressive effect of these agents on the central nervous system. In this study, we have used a pharmaco-electroencephalographic (EEG) method to examine the interaction of ethanol with levetiracetam. The influence of levetiracetam on the effect of ethanol on EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex) was determined. Levetiracetam was administered p.o. as a single dose (50 mg/kg or 200 mg/kg) or repeatedly at a dose of 100 mg/kg/day for 14 days. Ethanol was injected i.v. at a dose of 0.8 g/kg 60 min after the administration of levetiracetam. Ethanol caused an increase in the low frequencies (0.5–4 Hz) in the recording, as well as a marked decrease in the higher frequencies (13–30 Hz and 30–45 Hz). Changes in the EEG recordings after levetiracetam alone were more significant when the drug was given in repeated doses. Combined administration of ethanol and levetiracetam (200 mg/kg) resulted in a markedly synergistic effect in the frontal cortex and the midbrain reticular formation. The drug decreases the sensitivity of the hippocampus to ethanol, an observation that may be important in the treatment of alcohol addiction.

Protective Effects of Garlic Oil against Liver Damage Induced by Combined Administration of Ethanol and Carbon Tetrachloride in Rats

Herbs are known to play a vital role in the management of various liver diseases. Garlic oil (GO) contains numerous organosulfur compounds with potential hepatoprotective effects. The present work was planned to evaluate the possible preventive role of GO on biochemical and histopathological alterations induced by combined administration of ethanol (EOH) and carbon tetrachloride (CCl4) in rat liver. Two dose levels of GO (5 or 10 mg/kg/day) were administered orally to rats for 7 consecutive days with EOH + CCl4-induced liver damage. Activity of GO against liver damage was compared with that of silymarin (25 mg/kg/day, p.o. for 7 consecutive days). Biochemical parameters including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (γ–GT), alkaline phophatase (ALP) and bilirubin were estimated to assess the liver function. In addition, the level of total proteins, triglycerides, total cholesterol, glutathione (GSH), and thiobarbituric acid reactive substances (TBARS), in liver tissues were estimated. Liver damage was evidenced by an increase in the activity/level of AST, ALT, γ-GT, ALP and bilirubin in sera of rats after the combined administration of EOH and CCl4 compared to normal animals. Pretreatment of rats with GO reduced the EOH + CCl4-induced elevated levels of the above indices. Similarly, GO significantly prevented the decline in total proteins and the increase in triglycerides and total cholesterol resulted after EOH + CCl4 administration in rat liver homogenates. In addition, GO pretreatment restored liver GSH levels decreased due to EOH + CCl4 administration. The elevation in liver TBARS level due to EOH + CCl4 administration was also prevented by pretreatment with both low and high doses of GO. Histopathological examination indicated that GO exhibited an obvious preventive effect against the centrilobular necrosis and nodule formation induced by EOH + CCl4 administration. In conclusion, GO exerts hepatoprotective actions against EOH + CCl4-induced toxicity in rats.

Protective Effects of Garlic Oil against Liver Damage Induced by Combined Administration of Ethanol and Carbon Tetrachloride in Rats

Herbs are known to play a vital role in the management of various liver diseases. Garlic oil (GO) contains numerous organosulfur compounds with potential hepatoprotective effects. The present work was planned to evaluate the possible preventive role of GO on biochemical and histopathological alterations induced by combined administration of ethanol (EOH) and carbon tetrachloride (CCl4) in rat liver. Two dose levels of GO (5 or 10 mg/kg/day) were administered orally to rats for 7 consecutive days with EOH + CCl4-induced liver damage. Activity of GO against liver damage was compared with that of silymarin (25 mg/kg/day, p.o. for 7 consecutive days). Biochemical parameters including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (γ–GT), alkaline phophatase (ALP) and bilirubin were estimated to assess the liver function. In addition, the level of total proteins, triglycerides, total cholesterol, glutathione (GSH), and thiobarbituric acid reactive substances (TBARS), in liver tissues were estimated. Liver damage was evidenced by an increase in the activity/level of AST, ALT, γ-GT, ALP and bilirubin in sera of rats after the combined administration of EOH and CCl4 compared to normal animals. Pretreatment of rats with GO reduced the EOH + CCl4-induced elevated levels of the above indices. Similarly, GO significantly prevented the decline in total proteins and the increase in triglycerides and total cholesterol resulted after EOH + CCl4 administration in rat liver homogenates. In addition, GO pretreatment restored liver GSH levels decreased due to EOH + CCl4 administration. The elevation in liver TBARS level due to EOH + CCl4 administration was also prevented by pretreatment with both low and high doses of GO. Histopathological examination indicated that GO exhibited an obvious preventive effect against the centrilobular necrosis and nodule formation induced by EOH + CCl4 administration. In conclusion, GO exerts hepatoprotective actions against EOH + CCl4-induced toxicity in rats.

Comparison of the neurophysiological effects of allopregnanolone and ethanol in rats.

The central nervous system actions of allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one) and ethanol are at least partially mediated by modulation of gamma-aminobutyric acid (GABA)-A receptors. Although ethanol and allopregnanolone have similar behavioral effects, their macro-electrophysiological profiles have not been directly compared. The purpose of this study was to compare the effects of allopregnanolone and ethanol on the electroencephalogram (EEG) and event-related potentials (ERPs). Male Wistar rats were implanted with cortical and amygdalar electrodes. The rats were then administered allopregnanolone (0.0-10 mg/kg), ethanol (0.0-1.0 g/kg), or a combination of the two before recording. Allopregnanolone and ethanol had similar effects on ERPs. When administered alone, both decreased cortical P1-N1 ERP amplitude by 25-50% and N1 amplitude in the amygdala by 75-80%. Combined administration of ethanol (0.50 g/kg) and allopregnanolone (5.0 mg/kg), doses which were ineffective alone, decreased N1 amplitude in the amygdala by 60%. Allopregnanolone and ethanol had dissimilar EEG effects. Allopregnanolone increased high frequency power in the cortex and amygdala by 25-30%. Ethanol decreased cortical and amygdalar power in the same high frequency bands by 25-45%. Allopregnanolone, but not ethanol, also shifted cortical frequency in the 32- to 50-Hz band. Combined administration of allopregnanolone and ethanol had no effect on EEG power but enhanced allopregnanolone's effect on cortical frequency. These data suggest that allopregnanolone's macro-electrophysiological profile resembles barbiturates and benzodiazepines more than ethanol. Further, the interactions of allopregnanolone and ethanol appear complex, with multiple effects observed (enhancement or reversal) depending on the neurophysiological variable assessed.

The influence of the nitric oxide synthase inhibitor L-NOARG on the effects of ethanol in rats after acute ethanol administration.

The aim of this work was to study the effects of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (L-NOARG) on the sedative and toxic effects of ethanol in rats. Ethanol at a dose of 3 g/kg, intraperitoneally induced sleep in rats (sleep time: 111.2+/-10.3 min.). Administration of the nitric oxide synthase inhibitor L-NOARG (20 and 40 mg/kg, intraperitoneally) 30 min. before ethanol significantly increased the duration of ethanol-induced sleep. L-NOARG at doses of 20 and 40 mg/kg reduced the exploratory activity of rats in the open-field test and significantly enhanced the sedative effect of ethanol in this test. It is possible that this effect is not caused by the interaction of ethanol with nitric oxide pathways but by synergistic CNS depression caused by ethanol and L-NOARG. L-NOARG (20 and 40 mg/kg) had no effect on ethanol concentrations in blood after acute ethanol administration (2 and 3 g/kg). Moreover, the combined administration of ethanol (2 g/kg) and L-NOARG (20 and 40 mg/kg) caused a decrease in the body weight of animals, observed for 14 days. Also, livers of these rats were studied for necrosis and connective tissue reaction. In histological studies L-NOARG at a dose of 40 mg/kg had no effect on hepatic necrosis caused by the acute administration of ethanol but strengthened connective tissue reaction. L-NOARG is widely used in pharmacological studies, including those concerning the effects of ethanol. However, on the basis of our data the possibility of toxic interactions with ethanol should be considered.

The effects of the nitric oxide synthase inhibitor 7-nitroindazole on ethanol pharmacokinetics in rats after acute and chronic ethanol administration.

The aim of this work was to study the effects of the nitric oxide synthase (NOS) inhibitors 7-nitroindazole (7-NI) and NG-nitro-L-arginine (L-NOARG) on the effects and pharmacokinetics of ethanol in rats. Ethanol at a dose of 4 g/kg, i.p. induced sleep in rats (sleep time: 117.2+/-30.7 min). Administration of the NOS inhibitors 7-NI (20 mg/kg, i.p.) and L-NOARG (20 mg/kg, i.p.) 30 min before ethanol significantly increased the duration of ethanol-induced sleep. L-NOARG also significantly increased the toxicity of ethanol as evidenced by increased post-experimental lethality. Ethanol at a dose of 2 g/kg (i.p.) did not induce sleep in vehicle-treated rats; however, the combined administration of ethanol (2 g/kg) and 7-NI at doses of 40, 80, and 120 mg/kg caused sleep, for 49.4+/-3.7, 204.0+/-13.3, and 447.5+/-62.8 min, respectively. L-NOARG (20 mg/kg) had no effect on ethanol concentrations in blood after acute ethanol administration (4 g/kg). 7-NI in lower doses (20 and 40 mg/kg) had no effect and in higher doses (80 and 120 mg/kg) significantly slowed ethanol clearance during the 12 h after ethanol administration. The effect of 7-NI (20 mg/kg) on ethanol pharmacokinetics after chronic ethanol administration (inhalation for 18 days) was also studied. The administration of 7-NI immediately after the end of ethanol exposure had a pronounced effect on ethanol pharmacokinetics; in 7-NI-treated rats the fall in ethanol concentrations was significantly slower as compared with vehicle-treated rats. In 7-NI-treated rats, blood-ethanol levels were higher at 3, 6, 9, and 12 h after the end of ethanol exposure.

Interactions of Ethanol with Nicotine, Dizocilpine, CGP 40116, and 1-(m-Chlorophenyl)-biguanide in Rats

The present study examined the effect of ethanol (0.25–1.0 g/kg, IP) alone and in combination with drugs affecting different ligand-gated ion channels on a horizontal locomotor activity of male Wistar rats. None of the drugs given alone affected the locomotor activity. Similarly, combining ethanol either with nicotine (0.1 or 0.6 mg/kg, SC) or the competitive NMDA receptor antagonist, CGP 40116 (0.5 mg/kg, IP) did not result in any significant changes in ambulation. On the other hand, a significant hyperadditive interaction between ethanol (0.5 or 1.0 g/kg) and the uncompetitive NMDA receptor antagonist, dizocilpine (0.1 mg/kg, IP) was found. Thus, a combined administration of ethanol and dizocilpine produced a marked stimulation of the locomotor activity. Combining 1.0 g/kg ethanol with the 5-HT 3 receptor agonist, 1-(m-chlorophenyl)-biguanide (5.0 mg/kg, IP) tended to produce locomotor stimulation. Our results suggest the existence of interaction between ethanol and the NMDA receptor complex in mediation of locomotor stimulation. Alternatively, a common neurotransmitter system (other than glutamatergic) mediate central stimulatory effects of ethanol and dizocilpine. A possible role of dopamine in this interaction is being discussed.

Noradrenergic response to acute ethanol administration in heathly subjects: comparison with intravenous yohimbine

The effects of oral administration of ethanol [1.1 ml/kg 95% ethanol administered as a 20% (by volume) solution] and intravenous administration of the alpha 2 adrenergic receptor antagonist yohimbine hydrochloride (0.4 mg/kg), alone and in combination, were compared using a double-blind, placebo-controlled design. Twelve healthy subjects completed 4 test days during which drug effects on subjective measures of intoxication and anxiety, plasma levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and cortisol, and cardiovascular indices were assessed. Acutely administered oral ethanol significantly increased the subjective measures of intoxication and anxiety, plasma MHPG, and sitting systolic blood pressure compared with placebo. Intravenous yohimbine significantly increased subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and blood pressure relative to placebo. The ethanol-induced increase in plasma MHPG was significantly greater than that following yohimbine, whereas yohimbine resulted in significantly greater increases in anxiety, plasma cortisol, and blood pressure measurements than ethanol. The combined administration of ethanol and yohimbine had a clear additive effect of increasing the severity of acute intoxication compared with ethanol or yohimbine alone, and resulted in a significantly greater plasma MHPG response compared with either drug given alone. Although the pharmacokinetic effects of ethanol administration on NE metabolism must be considered, these findings suggest that the intoxicating and anxiogenic effects of acute ethanol administration may be associated with increased NE turnover, as measured by plasma MHPG, in healthy human subjects. In addition, these results indicate that ethanol and yohimbine may act additively to increase ethanol intoxication and that they may increase NE turnover through different physiological mechanisms.

Enhancement of the behavioral toxicity induced by combined administration of ethanol with methylxanthines: evaluation by discrete avoidance in mice.

Ethanol, at 1.6 and 3.2 g/kg p.o., disrupted the discrete lever-press and shuttle avoidances in mice, eliciting decrease in the avoidance rate. The response rate was increased by 3.2 g/kg of ethanol in the shuttle avoidance. The single p.o. administration of caffeine 3-30 mg/kg, theophylline 3-100 mg/kg, or theobromine 3-100 mg/kg produced no significant change in both response rate and the avoidance rate in the lever-press avoidance. In the shuttle avoidance, up to 3 mg/kg of caffeine, and 10 and 30 mg/kg of theophylline or theobromine significantly increased the response rate, though there was no significant change in the avoidance rate at any doses of these methylxanthines. Intermediate doses of methylxanthines ameliorated the ethanol (1.6 g/kg)-induced decrease in the avoidance rate with an increase in the response rate, indicating non-specific amelioration of the avoidance rate. The ethanol (3.2 g/kg)-induced decrease in the avoidance rate was enhanced by methylxanthines in a dose-dependent manner. However, in the shuttle avoidance, the response rate was sometimes increased by the combined administration of methylxanthines and ethanol. The present result suggest that, although ethanol and methylxanthines possess CNS depressant and stimulant actions, respectively, methylxanthines do not specifically ameliorate, but rather may worsen, the ethanol-induced avoidance disruption, indicating an enhancement of the behavioral toxicity.

Caffeine does not effectively ameliorate, but rather may worsen the ethanol intoxication when assessed by discrete avoidance in mice.

Ethanol disrupted the discrete lever-press and shuttle avoidances in mice at doses over 1.6 and 2.4 g/kg, p.o., respectively, eliciting a dose-dependent decrease in the % of avoidance with no significant change or slight increase in the response rate. Caffeine increased the response rate of both the avoidances at the doses of 1-30 mg/kg, p.o., but disrupted the avoidance at 100 mg/kg. Caffeine (10 mg/kg) reduced the decreased % of avoidance by ethanol (1.6 and 2.4 g/kg) with a significant increase in the response rate. In contrast, the % of avoidance was significantly lower after the combined administration of ethanol (3.2 g/kg) with caffeine than after ethanol (3.2 g/kg) alone. Unlike ethanol, diazepam (2 mg/kg, s.c.) and pentobarbital (10 mg/kg, s.c.) significantly decreased both the response rate and the % of avoidance. Caffeine (10 mg/kg) ameliorated the decreased response rate and the % of avoidance produced by diazepam and pentobarbital. The present results suggest that caffeine does not effectively ameliorate, but rather may worsen the ethanol intoxication.

Caffeine Does Not Effectively Ameliorate, but Rather May Worsen the Ethanol Intoxication When Assessed by Discrete Avoidance in Mice

Ethanol disrupted the discrete lever-press and shuttle avoidances in mice at doses over 1.6 and 2.4 g/kg, p.o., respectively, eliciting a dose-dependent decrease in the % of avoidance with no significant change or slight increase in the response rate. Caffeine increased the response rate of both the avoidances at the doses of 1–30 mg/kg, p.o., but disrupted the avoidance at 100 mg/kg. Caffeine (10 mg/kg) reduced the decreased % of avoidance by ethanol (1.6 and 2.4 g/kg) with a significant increase in the response rate. In contrast, the % of avoidance was significantly lower after the combined administration of ethanol (3.2 g/kg) with caffeine than after ethanol (3.2 g/kg) alone. Unlike ethanol, diazepam (2 mg/kg, s.c.) and pentobarbital (10 mg/kg, s.c.) significantly decreased both the response rate and the % of avoidance. Caffeine (10 mg/kg) ameliorated the decreased response rate and the % of avoidance produced by diazepam and pentobarbital. The present results suggest that caffeine does not effectively ameliorate, but rather may worsen the ethanol intoxication.

Enhancement of the Ambulation-Increasing Effect of Opioid Analgesics by Ethanol in Mice

The interaction between opioid analgesics (morphine and buprenorphine) and central depressants (ethanol, pentobarbital and diazepam) was investigated by means of ambulatory activity in mice. The ambulation-increasing effect of both morphine (10mg/kg, s.c.) and buprenorphine (1 mg/kg, s.c.) was enhanced by the combined administration of ethanol (0.8-3.2 g/kg, p.o.) in a dose-dependent manner. Naloxone (0.1 mg/kg, s.c.) was effective for reducing the enhanced ambulatory activity. The pretreatment with Ca-cyanamide (5 mg/kg. p.o., 30 min before) reduced the enhancement of the ambulation-increasing effect induced by the combined administration of opioid analgesics with ethanol, although it scarcely modified that of morphine and buprenorphine alone. On the other hand, neither pentobarbital (1-30 mg/kg, s.c.) nor diazepam (0.25-2 mg/kg, s.c.) modified markedly the ambulation-increasing effect of morphine and buprenorphine. The present results suggest that ethanol specifically interacted with opioid analgesics when the mouse’s ambulatory activity was used as the indicator.

Enhancement of the Ambulation-Increasing Effect of Opioid Analgesics by Ethanol in Mice.

The interaction between opioid analgesics (morphine and buprenorphine) and central depressants (ethanol, pentobarbital and diazepam) was investigated by means of ambulatory activity in mice. The ambulation-increasing effect of both morphine (10 mg/kg, s.c.) and buprenorphine (1 mg/kg, s.c.) was enhanced by the combined administration of ethanol (0.8-3.2 g/kg, p.o.) in a dose-dependent manner. Naloxone (0.1 mg/kg, s.c.) was effective for reducing the enhanced ambulatory activity. The pretreatment with Ca-cyanamide (5 mg/kg, p.o., 30 min before) reduced the enhancement of the ambulation-increasing effect induced by the combined administration of opioid analgesics with ethanol, although it scarcely modified that of morphine and buprenorphine alone. On the other hand, neither pentobarbital (1-30 mg/kg, s.c.) nor diazepam (0.25-2 mg/kg, s.c.) modified markedly the ambulation-increasing effect of morphine and buprenorphine. The present results suggest that ethanol specifically interacted with opioid analgesics when the mouse's ambulatory activity was used as the indicator.

Interaction of dichloromethane and ethanol in rats: toxicokinetics and nerve conduction velocity.

The influence of a single combined administration of ethanol (174 mmol/kg per os) plus dichloromethane (1.6, 6.2, or 15.6 mmol/kg p.o.) on blood concentrations of the tested substances and of carboxyhemoglobin, and on nerve conduction velocity was studied in rats. The blood alcohol concentration was not influenced significantly by dichloromethane. The single high dose of ethanol completely inhibited the carboxyhemoglobin concentration increase due to dichloromethane, but did not prevent the dichloromethane-induced decrease of nerve conduction velocity. It produced initially lower, then higher concentrations of dichloromethane in blood than values seen after administration of dichloromethane per se. Rats treated with ethanol plus dichloromethane showed a more pronounced decrease of nerve conduction velocity compared with rats administered dichloromethane only.

Encephalitis congenita symptomatica toxica in experimental conditions

The object of the study was the cerebral cortex of newborn rat. Tissue samples for examination were collected from the 2nd to the 8th hour after birth. Experimental material was the tissue of control animals and newborns whose mothers had been treated with both ethanol and pyrazole throughout gestation, and also with either ethanol or pyrazole alone. Ethanol and pyrazole were administered by gastric tube, ethanol at doses of 8.0 g/kg body weight, pyrazole at doses of 36 mg/kg body weight. The results indicate that ethanol ingested by the mother during gestation inhibits cell maturation in the cerebral cortex, whereas the combined administration of ethanol and pyrazole produces a highly toxic action. Its morphological exponent are symptoms which support the diagnosis of encephalitis congenita symptomatica toxica.

The interaction between ethanol and manganese in rat brain

The effect of combined administration of ethanol and manganese on the brain tissue of rats was investigated to evaluate the role of alcohol ingestion in inducing susceptibility to manganese poisoning. Ethanol and manganese alone and the combination of the two were administered orally daily to the rats for 30 days. Almost identical increase in the brain contents of manganese in rats receiving the metal alone and in combination with ethanol indicates that ethanol administration does not influence the accumulation of manganese in that organ. The copper contents of brain also increased to almost the same extent in these two groups. Synergistic effect of ethanol and manganese was noticed on increasing the activity of ATPase and RNase while marked antagonistic effect was observed on the activity of MAO. The mechanism and the significance of these neurochemical alterations occurring after the administration of ethanol and manganese have been discussed.