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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipoperoxidation, a degradative process of membranous polyunsaturated fatty acids, has been suggested to represent an important mechanism in the pathogenesis of ethanol toxicity on the liver and possibly also on the brain. Catalysis by transition metals, especially iron, is involved in the biosynthesis of free radicals contributing to lipid peroxidation. Although the exact nature of the redox-active iron implicated in this catalysis is still unknown, it has been well established that lipid peroxidation can be prevented in vitro by iron chelators such as desferrioxamine. Deprivation of redox-active iron through desferrioxamine inhibits by about 50% the microsomal oxidation of ethanol in vitro and reduces very significantly in vivo the overall ethanol elimination rate in rats. Administration of desferrioxamine together with ethanol also reduces the ethanol-induced disturbances in the antioxidant defense mechanisms of the hepatocyte. It also reduces in mice both the severity of physical dependence on ethanol and lethality following the acute administration of a narcotic dose of ethanol. Chronic overloading of rats with iron results, on the opposite, in an increased rate of ethanol elimination, although alcohol dehydrogenase and catalase activities are reduced and cytochrome P-450 depleted in the liver of such iron-overloaded animals. The magnitude of the ethanol-induced increase in lipid peroxidation and decrease in the major membranous antioxidant, alpha-tocopherol, is exacerbated in iron-overloaded rats. Several disturbances of iron metabolism have been reported in human alcoholics. Their contribution to ethanol toxicity appears very likely in the case of hepatic siderosis associated with alcohol abuse. Ethanol could however disturb iron metabolism even in the absence of gross abnormalities of the total iron stores. It is suggested that ethanol intoxication could increase cellular redox-active iron, thus contributing to an enhanced steady-state concentration of reactive-free radicals. This oxidative stress would lead to lipoperoxidative damage and cellular injury.
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PMID:Involvement of iron and iron-catalyzed free radical production in ethanol metabolism and toxicity. 303 5

Daily injections of the alcohol dehydrogenase inhibitor 4-methylpyrazole (4MP) were administered to C57BL/6J mice offered continuous free access to food, water and 10% v/v ethanol. There was a significant correlation (r = -0.82) between the rate of ethanol consumption during pretreatment and the effect of 4MP on subsequent intake. Mice drinking more than 2.5 g/kg per day decreased their intake, while subjects drinking less than this amount increased the quantity of ethanol self-administered. The elevated concentrations of plasma ethanol which resulted from voluntary consumption were sufficient to produce intoxication but did not induce physical dependence. Presenting mice with 10% ethanol as their only fluid or offering them a choice of water and saccharin-sweetened ethanol increased intake but failed to raise plasma ethanol to the concentrations observed in mice offered unflavored ethanol and water, and treated with 4MP. The evidence suggests that plasma ethanol does not limit voluntary drinking in untreated mice and that concentrations of 135 to 250 mg/dl are not avoided by C57 mice in a free-choice situation.
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PMID:Voluntary consumption of ethanol and its consequences in C57 mice treated with 4-methylpyrazole. 316 23

Young rats given ethanol chronically by gradually increasing the concentration in the drinking fluid to 17.5% reached a maximal daily consumption of 15-17 g ethanol/kg body wt., which corresponded to 35-40% of their energy intake. This chronic treatment was markedly potentiated by additional supplementation of the drinking fluid with a low dose of the alcohol dehydrogenase inhibitor 4-methylpyrazole. Rats on this regimen exhibited higher and more sustained blood ethanol levels. Consequently, more pronounced functional and metabolic tolerance developed and more frequent signs of physical dependence was observed than in rats drinking only ethanol solution. Simple provision of drinking fluid supplemented with ethanol and 4-methylpyrazole appears to provide a nutritionally adequate and easy way to produce tolerance and other chronic alcohol effects.
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PMID:A simple procedure using 4-methylpyrazole for developing tolerance and other chronic alcohol effects. 654 16

Although no animal model exactly duplicates clinically defined alcoholism, models for specific factors, such as the withdrawal syndrome, are useful for identifying potential neural determinants of liability in humans. The well-documented difference in withdrawal severity following chronic ethanol exposure, between the DBA/2J and C57BL/6J mouse strains, provides an excellent starting point for dissecting the neural circuitry affecting predisposition to physical dependence on ethanol. To induce physical dependence, we used a paradigm in which mice were continuously exposed to ethanol vapor for 72h. Ethanol-exposed and air-exposed (control) mice received daily injections of pyrazole hydrochloride, an alcohol dehydrogenase inhibitor, to stabilize blood ethanol levels. Ethanol-dependent and air-exposed mice were killed 7h after removal from the inhalation chambers. This time point corresponds to the time of peak ethanol withdrawal severity. The brains were processed to assess neural activation associated with ethanol withdrawal indexed by c-Fos immunostaining. Ethanol-withdrawn DBA/2J mice showed significantly (P<.05) greater neural activation than ethanol-withdrawn C57BL/6J mice in the dentate gyrus, hippocampus CA3, lateral septum, basolateral and central nuclei of the amygdala, and prelimbic cortex. Taken together with results using an acute model, our data suggest that progression from acute ethanol withdrawal to the more severe withdrawal associated with physical dependence following chronic ethanol exposure involves recruitment of neurons in the hippocampal formation, amygdala, and prelimbic cortex. To our knowledge, these are the first studies to use c-Fos to identify the brain regions and neurocircuitry that distinguish between chronic and acute ethanol withdrawal severity using informative animal models.
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PMID:Differential activation of limbic circuitry associated with chronic ethanol withdrawal in DBA/2J and C57BL/6J mice. 1980 Dec 71