Reduction of alcohol dependence in rats after carotid glomectomy

Carotid glomectomy significantly reduced the degree of alcohol addiction in rats, which was induced over 12 weeks. After glomectomy, the mean weekly volume of alcohol consumed by alcoholic animals over 4 weeks was lower compared to the preoperation level, while water consumption significantly increased by the 3rd and 4th weeks after surgery. Control sham operation had no effect on ethanol and water consumption in alcoholic rats. Possible involvement of the local renin-angiotensin system in chemoreceptor cells of the carotid body into systemic mechanisms of alcohol dependence is discussed. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 11, pp. 487–489, November, 2007     

IgA nephropathy in alcohol abuse. An animal model

In search of an animal model for alcohol abuse related IgA nephropathy, we investigated the Tsukamoto-French alcoholic rat. Continuous intoxication was induced by gastric infusion of a liquid diet with up to 47% ethanol in Wistar rats designated "alcoholic". Control animals received the same calorie count in the form of glucose. Animals were sacrificed after 6 or 10 weeks. IgA nephropathy was observed in 67% (10 of 15) of alcoholic rats and in none of 14 controls (p less than 0.0002). Alcohol abuse related renal changes, similar to those described in humans were present. These included mild mesangial expansion and intense IgA deposition. Foot process effacement was observed in alcoholic animals; severe proteinuria was found in half the animals with IgA nephropathy. This is the first report of chronic ethanol ingestion induced mesangial IgA nephropathy in an animal model.     

Protein turnover in brain during the development of alcohol dependence

The chronic effect of ethanol on central nervous system protein turnover was investigated in selected regions of brain following intoxication and withdrawal in a strain of ethanol preferring mice.Mice were serially injected with [¹⁴C]glucose in order to achieve a constant specific radioactivity of brain glutamase. Protein turnover was calculated from the specific activities of extracted protein and free glutamate.Results from these studies show that ethanol causes a significant increase in protein turnover in all sections of brain. The brain protein turnover in animals following alcohol withdrawal also shows an increase which deviates significantly from controls in 2 of the 3 regions examined.     

Alcoholic brain damage and neurological symptoms of alcohol withdrawal — Manifestations of overhydration

Central nervous system damage is a major complication of alcohol abuse. Vitamin deficiency, particularly thiamine deficiency, has a role in producing pathological and psychological changes of alcoholic brain damage, but it is likely that alcohol has a direct toxic effect on the brain. It is proposed that neuropathological abnormalities seen in alcoholics, and also neurological symptoms during alcohol withdrawal, may reflect cerebral edema caused by alcohol. The neurological symptoms of alcohol withdrawal show a similarity to those seen in hyponatremia or water intoxication. It is suggested that alcoholics show overhydration particularly during withdrawal and that pathological changes in the alcoholic brain are related to cerebral edema. Cerebral edema in withdrawing alcoholics may be caused by inappropriate section of vasopressin (antidiuretic hormone).     

Morphogenesis of pneumonia in alcoholic intoxication]

A single moderate dose of ethanol given to 120 Wistar male rats inhibits general immune defence and may facilitate the development of pneumonia. No morphological changes are found in the surfactant system in acute alcoholic intoxication. In chronic alcoholic intoxication with a pronounced withdrawal syndrome, apart from the decrease of general immune defence, lung surfactant system is damaged due to the direct ethanol effect on type II pneumocytes. These are the leading factors in the pneumonia pathogenesis characterized by a grave course and tendency to the abscess formation.     

Some biological mechanisms of the inborn predisposition to alcoholism

The children of alcoholism patients have a high biological risk of this illness, mental and emotional disorders, and behavioral disturbances. The offspring of white mongrel rats with chronic alcohol intoxication were investigated in order to study the neurochemical mechanisms of these phenomena. The content of DA in blood and blood plasma, the characteristsics of GABA and the opiate receptors of the brain, the activity of DBH, COMT, MAO, the content of cAMP and cGMP in brain tissue, as well as the expression of the gene c-fos were studied. Changes in the brain content of DA and qualitative and quantitative changes in MAO (an increase and solubilization of MAO A and B activity in the liver) were identified in the offspring of alcoholic rats. A tendency was also observed in the brain toward a decrease in the activity of DBH and COMT and an increase in the activity of cAMP and cGMP. The baseline expression of the gene c-fos in the offspring of male alcoholic rats did not differ from the norm; however, a powerful increase in the expression of the gene c-fos did appear in response to the administration of 2 g/kg of ethanol, in the absence of this effect in the control. A view is presented on the significant role of changes in the functions of the DA system in the genesis of pathology in the offspring of parents with chronic alcohol intoxication, as well as on the possible influence of the prolonged consumption of alcohol on the function of the genome. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 78, No. 12, pp. 30–38, December, 1992.     

Alcoholic lesions of the brain

Brains of 117 alcoholics admitted in the state of alcoholic coma or abstinence syndrome with an increase of blood pressure or development of acute psychosis were studied. The changes in the human brain were compared with those occurring in the brains of 30 rats with chronic alcoholic intoxication and formation of withdrawal syndrome. It is shown that in alcoholic coma and different manifestations of abstinence syndrome vascular and cellular changes take place, that can be attributed to the action of ethanol or its metabolites, as well as catecholamines. In the brain of the animals studied the same cellular and vascular changes were found as in the mentioned alcohol-induced manifestations in man. Progression of cephalic changes due to withdrawal syndrome is associated with more marked structural changes of the hemato-encephalic barrier.     

Mucosal immune dysfunction associated with alcoholic IgA nephropathy.

We investigated the hypothesis that alcohol-induced changes of the immune system result in IgA nephropathy (IAN). Wistar rats were infused with liquid diet containing alcohol: "alcoholics." Control rats received an isocaloric diet with glucose instead of alcohol. IAN was diagnosed by mesangial IgA deposition. When compared to controls, serum IgA in alcoholic rats with IAN had a fourfold increase and a twofold increase in alcoholics without IAN. The intestinal lamina propria showed overall lymphocyte depletion in alcoholic rats. The decrease was not uniform for all the lymphocyte subgroups: it resulted in a relative increase in IgA-B cells in alcoholic rats with IAN but not in alcoholic rats without IAN. No significant differences were observed between alcoholic and control rats in the percentages of spleen lymphocyte subtypes. We suggest that dysfunction of the mucosal immune system may be related to the induction of IAN in chronic alcohol consumption.     

Reflex insulin secretion due to central hyperglycemia promoted by intracarotid glucose infusion in dogs

The reflex insulin secretion was investigated by glucose infusions (10 ml of 3% solutions) into the carotid artery or the jugular vein in anesthetized and unanesthetized, untrained dogs. Neither intrajugular nor intracarotideal glucose infusions changed the peripheral glycemic level in any of the experiments. Reflex insulin secretion did occur when glucose was injected into the carotid artery under pentobarbital anesthesia (30 mg/kg IV), but not in unanesthetized animals. Saline infusion into the carotid artery or glucose into the jugular vein in both groups did not elicit a significant increase in insulin secretion.     

Glucagon attenuates the action of insulin on glucose output in the liver of the Goto-Kakizaki rat perfused in situ

The effects of glucagon and insulin on glucose production were explored directly using the isolated perfused liver of the Goto-Kakizaki (GK) rat, an animal model of type-2 diabetes. In the perfused liver of control rats, infusion of glucagon (0.06-1.0 nM) into the portal vein dose-dependently increased glucose output. In the GK rat liver, in which the intracellular distribution of glycogen was heterogeneous, basal glucose output during perfusion was significantly higher than in control, whereas the effect of glucagon on the maximum glucose output was not different. Infusion of insulin inhibited the glucagon-induced hepatic glucose output by 30-40% in control livers, but had no effect on that from the GK rat liver. The increase in hepatic cAMP content after glucagon infusion was antagonized by insulin in control livers, but not in the livers of GK rats. These results indicate that the antagonistic effect of insulin on glucagon-induced hepatic glucose production was attenuated in the isolated liver of the GK rat and suggest that this insulin resistance appeared in the signal transduction process of glucagon upstream from cAMP production.     

Mechanisms of the Influences of the Central Administration of Substance P on Ethanol Consumption in Chronically Alcoholic Rats

The effects of central administration of substance P (SP) on alcohol consumption and dopamine metabolism in the projections of the mesocorticolimbic and nigrostriatal systems of the brain were studied in chronically alcoholic rats. Rats received 15% ethanol solution for 6 months without choice. Intraventricular administration of SP (1 g/rat) decreased consumption of 10% ethanol solution by 41% compared with controls in an alcohol free choice test lasting one day. After chronic alcoholism, there was a decrease in the ratio of dihydroxyphenylacetic acid (DOPA) and homovanillic acid (HVA) to dopamine in the nucleus accumbens and striatum in rats subjected to alcoholism, as compared with intact controls. Chronically alcoholic rats treated with SP showed increases in DOPA, HVA, and the DOPA:dopamine and HVA:dopamine ratios in the nucleus accumbens as compared with animals given physiological saline, by 17%, 23%, 9% and 19% respectively. The only increases in the striatum were in the absolute levels of DOPA and HVA, by 28% and 29%, while the ratios of these metabolites to dopamine remained unchanged. Thus, central administration of SP decreased the voluntary consumption of ethanol in the ethanol free choice test and enhanced dopamine metabolism in structures of the mesolimbic and nigrostriatal systems in chronically alcoholic rats.     

Adrenocortical activation during long-term exercise in dogs: Evidence for a glucostatic mechanism

Summary Experiments were performed to elucidate the mechanism of changes in plasma 17-OHCS level during prolonged muscular exercise of moderate intensity. Dogs performed 120 min standard treadmill exercise. Plasma level of 17-OHCS increased during exercise. There was no change in the rate of removal of intravenously injected cortisol as compared with resting conditions. Exercise-dependent increase in plasma 17-OHCS level was prevented by continuous intravenous glucose infusion at a rate sufficient to prevent exercise hypoglycaemia. The same result was obtained when systemic hypoglycaemia persisted but glucose supply to the brain or liver was augmented by continuous glucose infusion to the carotid artery or portal vein. The same amount of glucose infused into a peripheral vein failed to abolish the adrenocortical response to exercise. The insulin-evoked hypoglycaemia of the magnitude comparable to that obtained during standard exercise did not significantly affect plasma 17-OHCS in resting animals.It is concluded that activation of glucocorticoid secretion during exercise is related to the glucostatic mechanism. Exercise hypoglacaemia per se is not responsible for adrenocortical activation. The results suggest that brain and hepatic glucoreceptors are engaged in the activation of the pituitary-adrenocortical system during exercise.     

The effect of glucose on the activity of the adrenal nerve and pancreatic branch of the vagus nerve in the rabbit

Efferent discharges were recorded from nerve filaments dissected from the adrenal branch of the splanchnic nerve and pancreatic branch of the vagus nerve. Infusion of glucose into the carotid artery caused a decrease in discharge rate of adrenal nerve and an increase of it in the pancreatic branch of the vagus nerve. No change in activity in both nerve branches was observed following infusion of mannose. An i.v. injection of glucose showed smaller effects. Glucose-sensitive neurons in the hypothalamus may play a role in these responses.     

Experimental studies on the influence of male alcoholism on pregnancy and progeny.

Chronic alcoholism was induced in male albino rats by an oral self-administration technique. Obvious signs of intoxication, withdrawal symptoms and reduced reproductive performance, as well as decreased serum glucose and serum testosterone levels, were observed in these animals. Notable differences were detected in prenatal mortality, mean litter size and sex ratio between the offspring of male alcoholic rats and the corresponding controls. In the alcohol-treated group the placental index was markedly reduced. However, the mean growth index showed no significant differences between the experimental and control groups.     

Effects of saltwort plants on blood plasma lipids in rats during chronic alcohol intoxication and after ethanol withdrawal

Saltwort plants (salsocollin) ameliorated plasma contents of total lipids, triacylglycerols, and phosphatidylcholine in rats with alcohol intoxication, but had no effect on cholesterol and total phospholipid levels. Salsocollin did not prevent the increase in the levels of total lipids and triacylglycerols 3 days after ethanol withdrawal. During abstinence, salsocollin potentiated symptoms of ethanol withdrawal (7 days later) in relation to the content of total phospholipids, but normalized the levels of phosphatidylcholine, phosphatidylethanolamine, and total lipids. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 6, pp. 665–667, June, 1999     

The mechanism of aminopyrine convulsions

Summary When injected into the common carotid artery the convulsive dose of aminopyrine in dogs was 2.5 mg/kg, while into the femoral artery or vein it was about 30 mg/kg. After unilateral ligation of the internal carotid artery the convulsive dose of aminopyrine injected into the ipsilateral common carotid artery increased greatly and even exceeded the intravenous dose. Following unilateral ligation of the external carotid artery a dose of less than 2 mg/kg of aminopyrine induced convulsions, when injected into the common carotid artery of the same side. The convulsive dose of aminopyrine was even lower (0.6 mg/kg) when injected directly into the internal carotid artery (following ligation of this vessel below the site of injection).Hence, the direct effect of this drug on the brain is to be regarded as the principal link in the mechanism of convulsions induced with aminopyrine.Presented by Active Member AMN SSSR V. N. Chernigovskii     

Selective increases in regional brain glucocorticoid: a novel effect of chronic alcohol

The hypothalamo-pituitary-adrenal axis shows functional changes in alcoholics, with raised glucocorticoid release during alcohol intake and during the initial phase of alcohol withdrawal. Raised glucocorticoid concentrations are known to cause neuronal damage after withdrawal from chronic alcohol consumption and in other conditions. The hypothesis for these studies was that chronic alcohol treatment would have differential effects on corticosterone concentrations in plasma and in brain regions. Effects of chronic alcohol and withdrawal on regional brain corticosterone concentrations were examined using a range of standard chronic alcohol treatments in two strains of mice and in rats. Corticosterone was measured by radioimmunoassay and the identity of the corticosterone extracted from brain was verified by high performance liquid chromatography and mass spectrometry. Withdrawal from long term (3 weeks to 8 months) alcohol consumption induced prolonged increases in glucocorticoid concentrations in specific regions of rodent brain, while plasma concentrations remained unchanged. This effect was seen after alcohol administration via drinking fluid or by liquid diet, in both mice and rats and in both genders. Shorter alcohol treatments did not show the selective effect on brain glucocorticoid levels. During the alcohol consumption the regional brain corticosterone concentrations paralleled the plasma concentrations. Type II glucocorticoid receptor availability in prefrontal cortex was decreased after withdrawal from chronic alcohol consumption and nuclear localization of glucocorticoid receptors was increased, a pattern that would be predicted from enhanced glucocorticoid type II receptor activation. This novel observation of prolonged selective increases in brain glucocorticoid activity could explain important consequences of long term alcohol consumption, including memory loss, dependence and lack of hypothalamo-pituitary responsiveness. Local changes in brain glucocorticoid levels may also need to be considered in the genesis of other mental disorders and could form a potential new therapeutic target.     

Effect of substance P on various vascular beds in the dog.

Using the electromagnetic flowmeter technique, the blood flow in the aorta, carotid, hepatic, superior mesenteric, renal and femoral arteries and portal vein was recorded during continuous i.v. infusion of synthetic Substance P (SP) in 8 dogs. Systemic and portal blood pressures were recorded. A significant decrease in mean arterial blood pressure was recorded at infusion of SP in the femoral vein at a rate of 2.5 ng x min-1 x kg b.w.-1 or higher. Portal venous blood pressure increased. A rapid increase in the carotid, hepatic, mesenteric and portal blood flow was obtained at infusion rates of 1.2 ng x min-1 x kg b.w.-1 or higher. The femoral artery responded with a late, transient increase in flow, with a return to the base level while the infusion was still in progress. The renal artery 0lood flow decreased slightly at low infusion rates and increased at higher. At SP infusions in the portal vein the infusion rate had to be increased to 20 ng x min-1 x kg b.w.-1 or higher before any general vascular reactions lere recorded, indicating that the liver has a high capacity for inactivating SP.     

Effect of induction of antibodies to serotonin on alcohol consumption and the status of the brain mediator system in rats with various degrees of alcohol motivation

Active immunization with serotonin-protein conjugate in rat experiments increased ethanol preference in animals with weak alcoholic motivation but reduced it in those with a high alcohol consumption. The level of antibodies to serotonin in blood was higher in alcohol-preferring rats than in water-preferring animals. The reduction of alcohol intake correlated with reduction of the level of 5-OH-indoleacetic acid in the animals' hypothalamus. It is assumed that the contrary effect of immunization with serotonin-protein conjugate on the alcoholic behavior of animals with a different initial level of alcoholic motivation is linked with the difference in their neurochemical organization.     

Feeding and arteriovenous differences of blood glucose in rats after injection with 2-deoxy-D-glucose and after food deprivation

Normal and adrenally demedullated rats injected with approximately 200 mg per kg of 2-deoxy-D-glucose (2-DG) ate just over 1 g more food than controls in 3-hr eating tests. This eating response was unaffected by delaying access to food by 30 min. Injections of 6-deoxy-D-glucose also increased eating, but less than 2-DG. Rats deprived of food for 24 hr ate about twice as much food as those injected with 2-DG. Drinking was increased following 2-DG in some but not all the experiments. Ether anaesthesia at the time of the injection depressed subsequent drinking but not eating. Arteriovenous differences of blood glucose (measured between carotid artery and jugular vein, and between carotid artery and femoral vein) were decreased after 24 hr deprivation of food, but slightly increased after injections of 2-DG. 2-DG stimulates eating without decreasing the rate of uptake of glucose from the blood.