Biomedical subjects

M Sarviharju

Publications and source records attributed to M Sarviharju.

26 records · Page 2Linked to original sources

PubMedDate not supplied

Revitalization of the AA and ANA rat lines: effects on some line characteristics.

After 37 generations, the AA and ANA rat lines developed for high and low voluntary alcohol consumption, were revitalized by crossing with hybrid (Brown Norwegian X Lewis) rats. The line difference in alcohol consumption continued, although initially diminished, after revitalization. The greater acetaldehyde accumulation and longer loss of righting reflex after ethanol administration of the ANAs persisted after revitalization, but significant line differences in motor impairment were no longer found. The line characteristics for open-field test behavior were also different than before revitalization. Of the previously-observed line differences that have now been reexamined, the level of blood acetaldehyde during ethanol metabolism appears to be the most closely related to the genetically-determined factors influencing alcohol consumption.

Acetaldehyde↗

PubMedDate not supplied

A simple procedure using 4-methylpyrazole for developing tolerance and other chronic alcohol effects.

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.

Animals↗

PubMedDate not supplied

Cerebellar GABAA receptors in two rat lines selected for high and low sensitivity to moderate alcohol doses: pharmacological and genetic studies.

Alcohol-sensitive (ANT) rat line produced by selective outbreeding for high acute sensitivity to the motor-impairing effects of ethanol, displays unusual cerebellar GABAA receptor pharmacology. The ANT rats have enhanced benzodiazepine agonist affinity at their binding sites for an imidazobenzodiazepine, [3H]Ro 15-4513, normally not affected by agonists at all, and reduced GABAA agonist, [3H]muscimol, binding, when compared to the alcohol-insensitive (AT) rat line. In the present study, the benzodiazepine receptor difference was localized to the cerebellar granule cell layer. This receptor difference was not found in ex vivo binding studies after lorazepam administration, although brain lorazepam concentrations in both rat lines similarly exceeded 1 microM. An indication for differential binding in vivo between the lines was, however, observed, as pretreatment with lorazepam accentuated the relative accumulation of radioactivity only in the cerebellum of the AT rat line after an intravenous injection of a trace amount of [3H]Ro 15-4513, thus revealing benzodiazepine insensitivity for a portion of the cerebellar [3H]Ro 15-4513 binding in the AT but not in the ANT rats. In the second generation of AT/ANT cross-breeding, there was no clear association of alcohol sensitivity and cerebellar receptor binding. There was, however, a significant positive correlation between the [3H]muscimol binding and the diazepam-insensitive [3H]Ro 15-4513 binding in the cerebellum. In conclusion, the receptor defect in the cerebellar granular cell layer of the alcohol-sensitive ANT rats was also detectable in vivo, but it may not explain the enhanced alcohol sensitivity of these rats.

Animals↗

PubMedDate not supplied

Ethanol sensitivity and consumption in F2 hybrid crosses of ANT and AT rats.

ANT rats that are highly sensitive to the motor-impairing effects of moderate ethanol doses voluntarily drink less ethanol in a free-choice test between 10% (v/v) ethanol solution and water than the ethanol-insensitive AT rats, suggesting the possibility that ethanol drinking is affected by initial ethanol sensitivity. However, in the F2 hybrid crosses of ANT and AT rats, voluntary ethanol drinking did not correlate with sensitivity to the motor-impairing effects of ethanol in the tilting plane test. Therefore, initial ethanol sensitivity does not appear to be a major factor in explaining variation in voluntary ethanol drinking.

Alcohol Drinking↗

PubMedDate not supplied

Phenotypic characterization of second generation offspring of alcohol-sensitive ANT and alcohol-insensitive AT rat lines.

The alcohol-sensitive ANT and the alcohol-insensitive AT rat lines developed by selective breeding for differential sensitivity to motor impairment on the tilting plane by a moderate ethanol dose (2 g/kg, IP), were cross-bred to produce second generation (F2) offspring to study phenotypic correlations between various behavioral and biochemical properties and the degree of initial alcohol sensitivity in the tilting plane test. The F2 population (n = 75) was subjected to alcohol sensitivity tests using a tilting plane test and a sleep time test, and to the elevated plus-maze test of sober activity and anxiety. Finally, the animals were sacrificed and the concentrations of dopamine and its acidic metabolites were analyzed in their striatal tissues. Serum corticosterone was determined to obtain information about the stress responses of the animals after the tilting plane test. The behaviors studied had no significant correlations with each other, suggesting that the various genetic and environmental factors affecting these behavioral phenotypes are different for each behavior. The biochemical measures yielded some correlations with the tilting plane test results that were contrary to the differences between the parent rat lines (dopaminergic indices) or that were confounded by the correlations with the body weight of the animals (corticosterone). Body-weight independent correlational tendency between the alcohol-induced impairment in motor performance and serum corticosterone concentration, however, fitted the differences between the parent lines, suggesting that stress mechanisms cannot be fully excluded as factors contributing to the differential alcohol sensitivity between the ANT and AT rat lines.

Animals↗

PubMedDate not supplied

Evidence of acetaldehyde-protein adduct formation in rat brain after lifelong consumption of ethanol.

Acetaldehyde, the first metabolite of ethanol, has been shown to be capable of binding covalently to liver proteins in vivo, which may be responsible for a variety of toxic effects of ethanol. Acetaldehyde-protein adducts have previously been detected in the liver of patients and experimental animals with alcoholic liver disease. Although a role for acetaldehyde as a possible mediator of ethanol-induced neurotoxicity has also been previously suggested, the formation of protein-acetaldehyde adducts in brain has not been examined. This study was designed to examine the occurrence of acetaldehyde-protein adducts in rat brain after lifelong ethanol exposure. A total of 27 male rats from the alcohol-preferring (AA) and alcohol-avoiding (ANA) lines were used. Four ANA rats and five AA rats were fed 10-12% (v/v) ethanol for 21 months. Both young (n = 10) and old (n = 8) rats receiving water were used as controls. Samples from frontal cortex, cerebellum and liver were processed for immunohistochemical detection of acetaldehyde adducts. In four (two ANA, two AA rats) of the nine ethanol-exposed rats, weak or moderate positive reactions for acetaldehyde adducts could be detected both in the frontal cortex and cerebellum, whereas no such immunostaining was found in the remaining five ethanol-treated rats or in the control rats. The positive reaction was localized to the white matter and some large neurons in layers 4 and 5 of the frontal cortex, and to the molecular layer of the cerebellum. Interestingly, the strongest positive reactions were found among the ANA rats, which are known to display high acetaldehyde levels during ethanol oxidation. We suggest that acetaldehyde may be involved in ethanol-induced neurotoxicity in vivo through formation of adducts with brain proteins and macromolecules.

Acetaldehyde↗

PubMedDate not supplied

Effects of lifelong ethanol consumption on rat locus coeruleus.

The effects of lifelong ethanol consumption and ageing on the morphology of locus coeruleus (LC) were studied in alcohol-preferring AA (Alko Alcohol) rats of both sexes. Ethanol (12% v/v) was the only available liquid for the ethanol-consuming rats from 3 months up to 24 months of age. Young (3-month-old) and old (24-month-old) control groups were included in the measurements. The LC morphometry was performed by an unbiased disector method. In the old control rats, the total neuron number, neuronal density and the volume of the LC proper did not differ from the young controls. In the ethanol-exposed rats, the total neuron number of the LC was decreased by 30% and the LC neuronal density by 22%, compared to the age-matched controls. No gender difference was found in the vulnerability of LC neurons to ethanol-induced degeneration. The results suggest a remarkable sensitivity of the LC neurons to the ethanol-induced degeneration in both male and female rats. The possible mechanisms and functional implications of this neuronal loss are discussed.

Aging↗

PubMedDate not supplied

Tolerance for the decrease in nerve conduction velocity and for the motor impairment produced by ethanol in mice: differential development during chronic ethanol consumption.

C57BL/6J/BOM mice were given 15% (w/v) ethanol solution as their sole drinking fluid. Nerve conduction velocities (NCV) and motor coordination (ataxia) of the unanesthetized animals were examined after a single IP injection of 3.0 g ethanol/kg body weight at 6, and 9 months after the start of drinking and after 3 months of abstinence. During chronic consumption of ethanol, tolerance for relative conduction time (RCT) change developed in six months. This tolerance was not observed after 9 months of ethanol treatment. The tolerance for ataxia persisted throughout the period of ethanol treatment. After a three month's abstinence, no differences between the controls and the animals previously on ethanol were observed regarding responses to acute ethanol administration. These observations suggest that different mechanisms underlie the development of tolerance for the effect of ethanol on peripheral nerve conductance and for the ataxia from ethanol in the central nervous system.

Alcoholism↗