Biomedical subjects

M Sarviharju

Publications and source records attributed to M Sarviharju.

At least 19 recordsLinked to original sources

PubMed2001

Increased behavioral neurosteroid sensitivity in a rat line selectively bred for high alcohol sensitivity.

Acute administration of a neurosteroid 5beta-pregnan-3alpha-ol-20-one induced a greater impairment in motor performance of the selectively bred alcohol-sensitive (ANT) than alcohol-insensitive (AT) rats. This difference was not associated with the sensitivity of gamma-aminobutyrate type A (GABA(A)) receptors, as 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone) decreased the autoradiographic signals of t-butylbicyclophosphoro[35S]thionate binding to GABA(A) receptor-associated ionophores more in the brain sections of AT than ANT rats. Nor was the difference associated with baseline levels of neuroactive progesterone metabolites, as 5alpha-pregnan-3,20-dione (5alpha-DHP) and 5alpha-pregnan-3alpha-ol-20-one were lower in the ANT rats. After ethanol (2 g/kg, i.p.) administration and the subsequent motor performance test, the increased brain concentrations of these metabolites were still lower in the ANT than AT rats, although especially in the cerebellum the relative increases were greater in the ANT than AT rats. The present data suggest that the mechanisms mediating neurosteroid-induced motor impairment are susceptible to genetic variation in rat lines selected for differences in ethanol intoxication.

Animals↗

PubMed2001

Dose-dependent decrease in glial fibrillary acidic protein-immunoreactivity in rat cerebellum after lifelong ethanol consumption.

The effects of aging and lifelong ethanol consumption on astrocytic morphology and glial fibrillary acidic protein-immunoreactivity (GFAP-IR) in the cerebellar vermis obtained from ethanol-preferring Alko, Alcohol (AA) rats were analyzed by using computer-assisted image analysis. The ethanol-consuming animals (both male and female) were given ethanol (10%-12%, vol./vol.) as the only available fluid for 21 months (3-24 months), whereas the young (3 months) and the old (24 months) controls received water. In the male rats, but not in the female rats, an age-related decrease in GFAP-IR was found in folia II, VII, and X of the molecular layer, and in turn, an age-related increase was found in folium X of the granular layer, indicating opposite changes in GFAP-IR for male rats due to aging in adjacent brain regions. In the female rats, 21 months of daily average ethanol consumption of 6.6 g/kg resulted in decreased GFAP-IR in folium VII of the molecular layer, and the decrease in cerebellar GFAP-IR correlated with the average daily ethanol intake (r=-.886, P=.019) when folia II, IV, VII, and X were analyzed together. No effect of ethanol on GFAP-IR was detected in the granular layer or in the central white matter of the female rats. There was no change in GFAP-IR in any of the three cerebellar layers of the male rats with average daily ethanol consumption of 3.2 g/kg. These results indicate that the Bergmann glial fibers are the GFAP-expressing structures of the cerebellum most sensitive to moderate-to-heavy chronic ethanol exposure and that this effect is dose dependent.

Age Factors↗

PubMed2001

Effects of lifelong ethanol consumption on drinking behavior and motor impairment of alcohol-preferring AA and alcohol-avoiding ANA rats.

The effects of drinking ethanol throughout a lifetime on voluntary drinking behavior and ethanol-induced motor impairment were studied in alcohol-preferring AA (Alko, Alcohol) and alcohol-avoiding ANA (Alko, Non-Alcohol) rats of both sexes. At the age 3 months, the rats were tested for individual voluntary ethanol (10% vol./vol.) intake and ethanol-induced motor impairment (2 g/kg, i.p.). The rats were housed in group cages, half of them having 12% (vol./vol.) ethanol as the only source of fluid and the other half having free access to water. Food was always available for all animals. At the age of 23 months, their individual voluntary ethanol intake and ethanol-induced motor impairment were tested again. During forced drinking, the females of both strains consumed more ethanol than did the males. The ethanol consumption of the AA and ANA females and the ANA males increased significantly (P < .001) with age, but a slight decrease was seen in the ethanol consumption of the AA males. Time x strain interaction showed a significant (P < .05) difference in the ethanol consumption of male rats, with the AA males having a slight decrease in ethanol consumption with age, whereas the ANA males increased their ethanol consumption. After 19 months of forced ethanol exposure, AA males significantly decreased their individual voluntary ethanol consumption, and individual voluntary ethanol consumption by ethanol-exposed AA males was more pronounced (P < .001) than that of the AA rats that had free access to water (P < .05). For the female AA rats, those having free access to water significantly decreased their voluntary ethanol consumption (P < .05), but those having ethanol only did not. No significant changes in voluntary ethanol consumption with age or with different exposures were seen in the ANA rats. Body weights were higher in the groups having access to water than in the ethanol-only groups, but the differences were not significant within the AA and ANA strains. The ANA rats were significantly heavier in all groups. These results indicate that the voluntarily nondrinking ANA rats can drink almost as much ethanol as the voluntarily drinking AA rats when they are forced to drink ethanol and that lifelong forced ethanol drinking does not change their inherent drinking habits. When sensitivity to ethanol was measured with the tilting-plane test, the old AA female rats were more sensitive to ethanol than were the young ones. The young ANA females were more sensitive than the AA females when tested at 4 months. In males, aging did not produce any differences in ethanol sensitivity.

Aging↗

PubMed2000

Enhanced locomotor stimulation by NMDA receptor antagonists in alcohol-sensitive ANT rats.

The ability of the antagonists for the N-methyl-D-aspartate (NMDA) type of glutamate receptor to modulate locomotor activity were compared in alcohol-sensitive (or alcohol-nontolerant, ANT) and alcohol-insensitive (or alcohol-tolerant, AT) rat lines. Both rat lines showed altered locomotor activity after acute injections of a competitive antagonist (LY235959), a glycine-site antagonist (L-701,324), or noncompetitive antagonists [MK-801, phencyclidine (PCP), and ketamine] of the NMDA receptor. MK-801 at 0.5 mg/kg caused a strong increase in horizontal activity in both rat lines, the effect being significantly greater in the ANT rats. There was a subpopulation among AT rats that was almost completely unresponsive to MK-801. This insensitivity to MK-801 correlated with the lack of c-fos induction in the retrosplenial and cingulate cortices. Fos immunoreactive cells in these brain regions after MK-801 treatment were more numerous in ANT than AT rats, although c-fos induction in the inferior olivary nucleus was similar in all animals after MK-801. The ANT rats showed greater locomotor stimulation also after ketamine and LY235959, while stimulation induced by PCP and depression induced by L-701,324 did not differ between the rat lines. The data suggest that altered NMDA receptor-mediated processes may correlate with differences in innate alcohol sensitivity in the ANT/AT rat model.

Alcohol Drinking↗

PubMed1999

Cerebellar GABA(A) receptors and anxiolytic action of diazepam.

Alcohol-sensitive ANT rats have a point mutation in the cerebellum-enriched GABA(A) receptor alpha6 subunit, which makes this subunit and the ANT rats in vivo highly sensitive to benzodiazepine agonists. In the elevated plus maze test of anxiety, diazepam produced a greater anxiolytic response in the ANT rats than in the control, alcohol-insensitive AT rats. The ANT rats were less sensitive to the sedative effect of diazepam in the staircase test of exploration. The results thus suggest that the mutant cerebellar granule cell layer receptors can participate in GABA(A) receptor-activation-induced anxiolysis.

Analysis of Variance↗

PubMed1999

Enhanced benzodiazepine and ethanol actions on cerebellar GABA(A) receptors mediating glutamate release in an alcohol-sensitive rat line.

Granule cell axon terminals of rat cerebellum possess benzodiazepine-insensitive GABA(A) receptors mediating glutamate release. We have investigated the ability of benzodiazepines, ethanol and furosemide to modulate the function of these receptors in the cerebellum of alcohol-tolerant (AT) and alcohol-nontolerant (ANT) rats. AT and ANT synaptosomes, prelabeled with [3H]D-aspartate, were superfused with GABA and various drugs during the K+ -depolarization. GABA similarly enhanced [3H]D-aspartate overflow in AT (EC50 = 1.7 microM) and ANT (EC50 = 3.9 microM) rats in a bicuculline-sensitive manner. Diazepam or zolpidem, at 0.1 microM, potentiated GABA at the GABA(A) receptor of ANT rats, but were ineffective at the AT receptor. Zolpidem acted with great potency (EC50 = 13.6 nM). Ethanol, added at 50 mM, potentiated GABA in ANT rats, but it was inactive at the GABA(A) receptor of the AT cerebellum. Furosemide significantly inhibited the effect of GABA in ANT, but not in AT synaptosomes. Our results show that one GABA(A) receptor (the receptor sited on granule cell terminals which mediates glutamate release) exhibits functional responses to diazepam and ethanol that differ between AT and ANT rats. However, the data with zolpidem and furosemide differ from previous results obtained with membranes of the granule cell layer suggesting that distinct GABA(A) receptor subtypes may exist on axon terminals versus soma/dendrites of granule cells.

Animals↗

PubMed1999

Effects of lifelong ethanol consumption on rat sympathetic neurons.

In this experiment we studied the effects of aging and lifelong ethanol consumption on rat peripheral sympathetic neurons. The aim was to find out the possible differences in the vulnerability to ethanol-induced neuronal degeneration between rats of both genders, or between the alcohol-avoiding (ANA) and the alcohol-preferring (AA) lines of rat. The superior cervical ganglia (SCG) of 40 male and 41 female AA and ANA rats were analyzed. The ethanol-exposed groups had 12% ethanol as the only available fluid from 3 to 24 months of age. The young (3 months) and old (24 months) control groups had water instead. SCG neuronal density, volume, and total neuron number were measured by unbiased morphometric methods. No gender difference was seen in either the volume of the SCG or in the SCG neuron number. The volume of the ganglion was significantly increased with age, but the total neuron number did not change. Neuronal density was significantly decreased with age, but lifelong ethanol consumption induced no further decrease. SCG neuron number in the ethanol-exposed groups did not differ from the age-matched or young control groups, but a significant negative correlation (r = -0.70, p<0.01) was seen between individual ethanol consumption and the number of SCG neurons in the female rats. The amount of lipopigment in the SCG was increased in the ethanol-exposed male rats. These results suggest that the peripheral sympathetic neurons are rather resistant to ethanol-induced degeneration, and that no major gender or line differences exist in this respect.

Aging↗

PubMed1998

Lifelong ethanol consumption and loss of locus coeruleus neurons in AA and ANA rats.

The effects of lifelong ethanol exposure and aging on the morphology of the locus coeruleus (LC) were studied in the AA (Alko, Alcohol) and ANA (Alko, Nonalcohol) rats of both sexes. The ethanol-consuming (EtOH) rats were given 12% (v/v) ethanol as the only drinking fluid from 4 to 22 months of age, whereas the young (3-month-old) and aged (24-month-old) controls had only water available. The total LC neuron numbers were obtained by using the unbiased disector method. In the AA line, as we have previously reported. the EtOH female and male rats displayed a 26-30% loss of LC neurons compared with the controls. In the ANA line, the EtOH females had 30% fewer LC neurons than the controls (EtOH 1579 +/- 377 vs. controls 2264 +/- 269, ANOVA p < 0.01), whereas the EtOH males showed no neuron loss compared to the controls (EtOH 1848 +/- 525 vs. controls 2216 +/- 152, ANOVA NS). However, taking into account (sex by line ANCOVA) the markedly higher ethanol intake of the female rats in both lines, no gender or line differences in the ethanol-induced LC degeneration were detected. Neither was there any difference in LC neuron numbers between the young and old control rats of either line of rats. In conclusion, chronic alcohol consumption, not aging per se, damages the LC neurons in experimental animals.

Acetaldehyde↗

PubMed1998

Defensive burying and stress gastric erosions in alcohol-preferring AA and alcohol-avoiding ANA rats.

The aim of this study was to investigate differences in shock-prod induced defensive burying and vulnerability to stress gastric ulcerations in two lines of rats selectively bred for alcohol-preference (AA) and alcohol-avoidance (ANA). Alcohol-naïve animals from the AA and ANA lines were tested in the shock-prod defensive burying test and (after an interval of approximately 2 months) in a 75 min water-immersion stress ulceration-inducing procedure. The AA rats showed longer latencies (327.5 s) for burying after shock-prod compared with the ANA animals (128.0 s). Furthermore, the ANA rats developed more stomach ulcerations (12.35 mm) compared with the AA rats (1.30 mm). Animals also differed based on whether they had been tested for defensive burying or not, with the tested animals showing less ulceration development than the control group. We hypothesize that the difference between AA and ANA rats is controlled by some common biochemical mechanism. One likely candidate is the dopaminergic system, which is involved in both the motivational effects of alcohol, as well as anxiety and stomach ulceration. In addition, the alcohol-preferring strain seems to be less fearful and generally may be less sensitive to aversive stimuli, be it shock prod, the aversive properties of alcohol, or water immersion stress.

Alcoholism↗

PubMed1997

Effects of lifelong ethanol consumption on cerebellar layer volumes in AA and ANA rats.

Aging and chronic alcohol consumption can cause degenerative changes in the cerebellar cortex. In this study, the effects of aging and lifelong alcohol consumption on cerebellar cortical layer volumes (molecular and granular) and also white matter layer volumes were studied in alcohol-preferring (AA) and nonpreferring (ANA) rats of both sexes. The ethanol-consuming animals (EtOH) had 12% (w/v) ethanol as the only available fluid from 4 to 22 months of age, whereas the young (3 month) and old controls (24 months) had only water to drink. The volumes of molecular, granular, and white matter layers of the cerebellar vermis in folia II, IV, VII, and X were measured by using systematic sampling and a point-counting method. The volumes of the granular and white matter layers showed consistent increase between 3 and 24 months of age, whereas the volume of the molecular layer remained unchanged with increasing age. Individual ethanol intake was measured over a 1-week period at the beginning and at the end of chronic ethanol exposure. Significant (ANOVA, p = 0.000) sex difference was found in the drinking behavior in both lines, with females consuming more alcohol than males (daily ethanol consumption at 22 months of age 3.2 +/- 0.3 vs. 7.1 +/- 0.3 g/kg for AA males and females; 3.2 +/- 0.3 vs. 5.4 +/- 0.4 g/kg for ANA males and females, respectively). The only ethanol-induced effect on the cerebellum was observed in ANA-EtOH females with a 15% reduction in the volumes of the molecular and granular layer in folium II compared with age-matched controls and a significant (p < 0.05, analysis of covariance with ethanol intake as a covariate) line difference in folium II (molecular and granular layers) was observed between ANA-EtOH females and AA-EtOH females. Furthermore, the volume of the molecular layer in folium II was significantly (p < 0.05, analysis of covariance with ethanol intake and body weights as covariates) reduced for ANA-EtOH females, compared with ANA-EtOH males indicating a sex difference in the cerebellar degeneration due to chronic alcohol consumption. Of the three layers studied, the white matter layer was the most resistant layer to the effects caused by chronic alcohol consumption. In view of the fact that AA and ANA rats of both sexes differ regarding the drinking behavior and ethanol metabolism, they provide an important model for further research on ethanol-induced pathological changes in the central nervous system.

Acetaldehyde↗

PubMed1996

Alcohol drinking is reduced by a mu 1- but not by a delta-opioid receptor antagonist in alcohol-preferring rats.

To assess the roles of opioid receptor subtypes in voluntary alcohol drinking, alcohol-preferring AA (Alko, Alcohol) rats, non-deprived of food or water, were used in a paradigm where access to 10% alcohol solution was limited to 1-4-h sessions on every 2nd working day. The delta-opioid receptor antagonist naltrindole (1-5 mg/kg i.p. 15 min before the session) had no effect on alcohol drinking, while it attenuated the delta-opioid receptor agonist [D-Pen2, D-Pen5]enkephalin-induced locomotor stimulation. The mu1-opioid receptor antagonist naloxonazine (1-15 mg/kg i.p. 20 h before the session), at the largest dose, decreased alcohol drinking. It also decreased food intake. When naltrindole (1 mg/kg) and naloxonazine (15 mg/kg) were given prior to 3 consecutive sessions, the former had no effects at any session. Naloxonazine decreased alcohol consumption only in the 1st session, although the reduction of daily water intake became stronger during repeated administration. 4 days after the last drug administration, naloxonazine-treated animals consumed alcohol nearly twice as much as in the control session before any drug treatment. These data suggest that delta-opioid receptors are not involved in the regulation of alcohol drinking in AA rats. mu1-Opioid receptors may be involved in alcohol drinking, although the data suggest that even their prolonged blockade alone is insufficient to induce a sustained decrease in alcohol drinking.

Alcohol Drinking↗

PubMed1996

Pharmacologic actions of subtype-selective and novel GABAergic ligands in rat lines with differential sensitivity to ethanol.

Alcohol-nontolerant (ANT) rats, produced by selective breeding for high sensitivity to motor-impairing effects of ethanol, have a point mutation in the cerebellar gamma-aminobutyric acid type A (GABAA) receptor alpha 6 subunit, which has been proposed to underlie enhanced sensitivity to benzodiazepine agonists as well. We compared ANT and alcohol-tolerant (AT) rats using behavioral and neurochemical methods to assess the significance of alpha 6- and non alpha 6-containing GABAA receptor subtypes. Motor performance in a tilting plane test was largely unaffected by a type I benzodiazepine receptor-preferring agonist, zolpidem [1-10 mg/kg, intraperitoneally (IP)], partial benzodiazepine agonists bretazenil and ZG-63 (both at 40 mg/kg, IP), and a novel broad-spectrum anticonvulsant loreclezole (40 mg/kg, IP) in both ANT and AT rats. In contrast, diazepam (10 mg/kg, IP) impaired performance of the ANT but not AT animals. These data, supported by results from brain regional autoradiography of [3H]Ro15-4513 and membrane binding of [3H]ZG-63 and [35S]TBPS as influenced by these ligands, strongly suggest that only ligands with full agonist actions on mutant (ANT) but not wild-type (AT) alpha 6-containing GABAA receptors are able to produce motor impairment in the ANT rats.

Animals↗

PubMed1994

Effects of lifelong ethanol consumption on the ultrastructure and lipopigmentation of rat heart.

The myocardial interactions of ageing and lifelong ethanol ingestion were studied in the ethanol-preferring AA (Alko Alcohol) line of rats. Samples of the left ventricle from young control rats (3-month), old control rats (30-month) and rats exposed to ethanol from 3 to 30 months of age, were studied in terms of myocardial ultrastructure and lipopigmentation. Electron microscopic morphometry showed an age-related increase in the volumetric densities of lipofuscin and unspecified sarcoplasm, while the proportions of mitochondria, myofibrils and tubular structures remained unaltered in the left ventricular myocardium. Lifelong ethanol exposure increased the proportion of sarcoplasmic reticulum and transverse tubules, apparently due to dilation of the tubular structures. Mitochondria were significantly larger in the ethanol-exposed rats compared to the control rats of the same age, while the volumetric proportion of mitochondria tended to decrease in the ethanol-exposed group. Fluorescence microscopic image analysis showed that myocardial lipopigmentation (proportion of myocardial area covered by autofluorescent lipopigments) was about two-fold in the old ethanol-exposed rats compared to the old control rats, and 13-fold compared to the young controls. It is concluded that ageing and chronic ethanol ingestion produce rather different patterns of alteration in myocardial ultrastructure, which does not support the concept of ethanol-induced accelerated ageing. The enhancement of myocardial lipofuscin accumulation is thought to reflect chronic oxidative stress in the hearts exposed to ethanol.

Age Factors↗

PubMed1992

Interaction of aging and lifelong ethanol ingestion on ethanol-related behaviors and longevity.

The interactions of aging and long-term voluntary ethanol consumption were studied in the alcohol-preferring AA (Alko Alcohol) rats. The mean daily ethanol intake was 6.45 +/- 0.31 g/kg/day (mean +/- SE) at the beginning of the exposure at 3 months of age. The control animals were given only food and water ad libitum. There was no difference in survival or weight gain between the control and ethanol groups. When tested for voluntary ethanol intake at the age of 24 months, the rats in the ethanol group consumed significantly more ethanol than the controls. The two groups did not differ in ethanol-induced motor impairment, sleep-time, or hypothermia, nor in the rate of ethanol elimination. The 24-month-old animals, however, showed higher sensitivity to ethanol than the 3-4-month-old rats in the sleep-time test. It is concluded that the feeding regimen used in this study did not produce any detectable interactions between ethanol and the aging processes in the AA rats.

Aging↗

PubMed1987

Alcohol-preferring (AA) and alcohol-avoiding (ANA) lines of rats after introgression of alien genes.

Outcrossing has been used as a method for introducing new genetic variability into the high-drinking AA and low-drinking ANA rat lines that had reached their selection limits and were suffering of poor fertility and decreased litter size. The response to the renewed selection for differential alcohol consumption, and the effect of outcrossing upon the components of productivity are reported.

Alcohol Drinking↗

PubMed1986

Enzymes of catecholamine metabolism in the brains of rat strains differing in their preference for or tolerance of ethanol.

The activities of the catecholamine-synthesizing and inactivating enzymes were determined in whole brains of two pairs of rat strains differing in their genetically-determined behavioural responses to ethanol. The alcohol-tolerant (AT) rats did not show any significant differences in enzyme activities when compared with the non-tolerant (ANT) strain. The activity of tyrosine hydroxylase was found to be significantly higher in brains of the alcohol-preferring (AA) rats, than in those of the alcohol-non-preferring (ANA) strain.

Animals↗

PubMed1983

Alcoholic neuropathy and hepatopathy in mice. An experimental study.

Seventeen young adult C57BL male mice were given 15% (w/v) solution of ethanol as their sole drinking fluid for seven to nine months. C57BL male mice given regular drinking water were used as controls. After decapitation samples from the livers and the sciatic nerves of the mice were processed for electron microscopy and morphometry. The ultrastructural analysis revealed slight alterations in the nerves of the ethanol-exposed mice. The changes were mostly in the Schwann cells. Pathological Schwann cell-axon relationships were also more abundant in the ethanol-exposed mice. The thickness distribution of the myelinated nerve fibers was similar in the exposed and the control mice. The transverse-sectional area of hepatocytes was greater in the mice on ethanol than in the controls. The volume density of lipid vacuoles of the liver cells was significantly increased in the mice treated with ethanol (p less than 0.001). The hepatic changes indicate a significant effect of ethanol on the liver. The findings suggest that, in mice, chronic peroral treatment with ethanol can produce slight changes suggesting peripheral neuropathy together with fatty metamorphosis of the liver.

Alcoholism↗

PubMedDate not supplied

Motor impairment, narcosis and hypothermia by ethanol: separate genetic mechanisms.

The AT and ANT rat lines, developed by selective outbreeding for differential ethanol-induced motor impairment, were tested for their sensitivity to the hypothermic and narcotic (loss of righting reflex) effects of ethanol. In contrast to the large differences between the lines in their degree of motor impairment, as measured with both the tilting-plane and rotarod tests, only minor differences were observed in duration of loss of righting reflex or hypothermia. Therefore, we suggest that genetically determined factors influencing motor impairment are for the most part dissociated from the factors determining the hypothermic and narcotic effects of ethanol.

Alcoholic Intoxication↗