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Biomedical subjects

A Kosobud

Publications and source records attributed to A Kosobud.

At least 19 recordsLinked to original sources
PubMed1990

Estimation of genetic correlation: interpretation of experiments using selectively bred and inbred animals.

There is increasing interest in determining the extent to which multiple characters related to drug sensitivity are influenced by common genes. The principal method for testing for the existence of such genetic correlations has been examination of pairs of mouse or rat lines selectively bred for sensitivity or resistance to a single behavioral effect of a drug. When a pair of selected lines is found to differ significantly on some trait other than the one on which they were selected, it is commonly concluded that significant genetic correlation between the traits exists, implying the action of a common set of genes on the two responses. In addition, results from comparisons of lines of animals selected for trait X and tested for trait Y may be compared with results from lines selected for trait Y and tested for trait X. As the number of correlated responses in selected lines increases, it becomes more important to adhere to sensible, consensual guidelines for interpreting such line differences. The principles underlying phenotypic and genotypic correlational analyses with selected lines are discussed. A scheme is presented to allow standardization across laboratories of inferences about the relative strength of genetic association from experiments with selected lines. Statistical and practical experimental issues are addressed. Estimates of genetic correlations may also be derived from the correlation of mean trait values across a panel of inbred strains. Existing data have sometimes found estimates of genetic correlations made with one approach to be inconsistent with those estimated in other ways. Possible reasons for this are discussed. Finally, the relationship between phenotypic correlations and genetic correlations is discussed. Phenotypic and genetic correlations for a pair of traits may differ widely, and may even be opposite in sign. Both are characteristic of the population from which they are sampled. Phenotypic correlations estimated within selected lines may change over time, as the additive genetic variance in the selected trait is exhausted. A specific example of this phenomenon is given.

Alcoholic Intoxication↗
PubMed1989

The effect of ethanol on behavioral temperature regulation in mice.

Mice were injected with 20% ethanol in 0.9% NaCl, or with 0.9% NaCl without ethanol during sessions of behavioral thermoregulation in a tubular temperature gradient (ambient temperature range approximately 9-38 degrees C). Internal temperature was monitored with an implanted telemetry device. An imaging system recorded the position (selected temperature) of the mouse within the gradient every 5 sec. A dose of either 2.25 or 2.60 g ethanol/kg body wt. produced significantly lower body temperatures than control (NaCl) injections. The 2.60 g/kg dose produced significantly lower selected temperatures than either the NaCl or 2.25 g/kg injections. Doses of 2.75 g ethanol/kg and above incapacitated the mice, precluding accurate behavioral thermoregulation. Utilizing a thermoregulatory index to compare the responses following experimental and control injections indicated that 2.25 or 2.60 g ethanol/kg leads to a decrease in the regulated temperature of mice.

Animals↗
PubMed1988

Voluntary consumption of ethanol in WSP, WSC and WSR selectively bred mouse lines.

The genetic correlation between voluntary consumption of ethanol solutions and severity of withdrawal seizures after chronic ethanol exposure was assessed using the selectively bred Withdrawal Seizure Prone (WSP) and Resistant (WSR) mouse lines. WSP mice have at least ten-fold more severe withdrawal than WSR mice after equal chronic ethanol exposure, and withdrawal in a nonselected control line (WSC) is intermediate to withdrawal in the WSP and WSR lines. In the first experiment, mice from the WSP, WSC and WSR lines were offered a choice between 2.2, 4.6 and 10.0% ethanol solutions and water in three consecutive eight-day sessions. WSR mice consumed more ethanol than WSP mice, and WSC mice were intermediate. In a second experiment, WSP and WSR mice were offered ethanol solutions in concentrations that were adjusted up or down every two days depending upon the amount of ethanol consumed. WSP and WSR mice displayed very different patterns of drinking, with WSP mice drinking more ethanol in early stages of the experiment, and WSR mice drinking more ethanol later. Results of these experiments suggest that some genes influencing severity of withdrawal from ethanol also influence voluntary ethanol drinking.

Alcohol Drinking↗
PubMed1987

Mice genetically selected for differences in open-field activity after ethanol.

Starting from a population of genetically heterogeneous mice, selective breeding is being used to develop lines differing in sensitivity to ethanol-induced open-field activity. Mice are tested twice for 4 min in an open field. The first test is between min 2-6 after injection of saline. Twenty-four hr later, a similar test is performed after injection of ethanol (1.5 g/kg). Two independent FAST lines are being selected for ethanol-induced increases in activity, and two independent SLOW lines are being selected for ethanol-induced decreases. After four generations of selection, the lines have diverged significantly. These lines should be useful for exploring the neuropharmacological basis for the activating and rewarding properties of ethanol.

Animals↗
PubMed1987

Genetic selection of mouse lines sensitive (cold) and resistant (hot) to acute ethanol hypothermia.

Using the technique of within-family selective breeding, we have generated mouse lines that differ genetically in sensitivity to the acute hypothermia induced by injection of 3 g/kg ethanol (EtOH). After 5 generations of selection, the difference in maximal hypothermic response between COLD and HOT lines was 1.6 degrees C in the first replicate and 1.2 degrees C in the second replicate. Estimates of realized heritability were h2 = .17 in each replicate. No differences in EtOH metabolism have developed, so the differences between HOT and COLD mice are presumably in neurosensitivity. These lines of animals should be useful for studying the biological mechanisms underlying neurosensitivity to EtOH. In conjunction with other selectively bred lines, they should improve our understanding of the genetic relationships among EtOH neurosensitivity, tolerance and physical dependence.

Animals↗
PubMed1986

Genetic differences in anticonvulsant sensitivity in mouse lines selectively bred for ethanol withdrawal severity.

WSP (withdrawal seizure-prone) mice exhibit approximately 10-fold more severe withdrawal convulsions than WSR (withdrawal seizure-resistant) mice after identical chronic ethanol exposure. Although WSP and WSR mice do not differ in threshold for seizures elicited by electroconvulsive shock (ECS), WSR mice are more sensitive to ethanol-induced elevation of ECS seizure thresholds. The current experiments demonstrated that WSR mice showed more ECS-induced seizure threshold elevation than WSP mice when tested after the administration of C1-C5 straight-chain alcohols. Whereas the brain concentrations of the C1 and C2 alcohols did not differ between the lines, WSP mice tended to have higher brain concentrations than WSR mice of the C3-C5 alcohols, even though they exhibited the smaller behavioral response in all cases. Thus, the difference between WSP and WSR mice was one of neurosensitivity and could not be attributed to pharmacokinetic differences. The WSR line was also more sensitive to ethchlorvynol, methyprylon, barbital, phenobarbital, pentobarbital, diazepam, valproic acid and phenytoin in this test. Examining loss of righting reflex (RR), we found that WSP and WSR mice did not differ in ED50, latency to lose RR or duration of loss of RR. Thus, the genetic anticonvulsant sensitivity difference is not simply a genetic difference in sensitivity to central nervous system depression between the lines. In summary, WSR mice were more sensitive to the anticonvulsant effects of a variety of compounds than WSP mice, suggesting that some genes influence both ethanol withdrawal seizures and ethanol's anticonvulsant effects.

Alcohol Withdrawal Delirium↗
PubMed1986

Ethanol withdrawal in mice bred to be genetically prone or resistant to ethanol withdrawal seizures.

We are engaged in a selective breeding program developing lines of mice which differ in severity of withdrawal convulsions after ethanol treatment. Withdrawal seizure prone (WSP) mice show greater handling-induced convulsion scores than withdrawal seizure resistant (WSR) mice after 3 days of ethanol intoxication. In the present experiments, we sought to characterize these mice further as a model of genetic susceptibility to ethanol dependence and withdrawal. During withdrawal after chronic treatment with ethanol, WSP mice displayed more severe handling-induced convulsions and tremor than WSR mice, and tended to show greater reduction of exploratory activity. WSP and WSR mice did not differ in ethanol metabolism after acute treatment with ethanol alone or after chronic treatment with ethanol and pyrazole, an alcohol dehydrogenase inhibitor. Six to 10 hr after an acute injection of ethanol, WSP and WSR mice showed elevated handling-induced convulsions. This elevation was more pronounced in WSP mice than in WSR mice. WSP mice also showed slightly more severe convulsions than WSR mice when treated with saline or pyrazole alone. In summary, WSP and WSR mice treated with identical doses of ethanol differ in several symptoms of withdrawal, whereas not differing in ethanol metabolism. These mice constitute a useful population in which to study the molecular mechanisms of ethanol dependence and withdrawal.

Alcohol Withdrawal Delirium↗
PubMed1986

Sensitivity and tolerance to ethanol in mice bred to be genetically prone or resistant to ethanol withdrawal seizures.

Mice genetically susceptible (withdrawal seizure prone; WSP) and resistant (withdrawal seizure resistant; WSR) to ethanol (EtOH) withdrawal convulsions have been developed by selective breeding. WSP mice show much more severe EtOH withdrawal than WSR mice after equal intensities of exposure to EtOH. The present experiments report a systematic comparison between WSP and WSR mice with respect to their neurosensitivity to two effects of EtOH, EtOH-induced hypothermia (HT) and loss of righting reflex (RR). The degree of tolerance developed to these effects was also compared between the lines. WSP and WSR mice did not differ in sensitivity to EtOH-induced HT. When EtOH was administered daily for 3 days, both lines developed tolerance as evidenced by attenuated HT, but there was no line difference. Because blood EtOH concentrations did not change, the tolerance was functional rather than pharmacokinetic. When twice-daily injections were given for 4 days before testing on the 5th day in an effort to increase the degree of tolerance achieved, functional tolerance was slightly greater in the WSR line than in the WSP line 90 to 120 min, but not 30 to 60 min, after EtOH. In similar experiments, WSP and WSR mice were found to have the same ED50 to EtOH-induced loss of RR. The brain EtOH concentrations of WSP and WSR mice were the same at the time RR was lost and at the time RR was regained. Thus, neither line developed acute functional tolerance to this effect of EtOH. WSR mice lost RR more quickly than WSP mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Ethanol dependence and the pituitary-adrenal axis in mice. I. Genotypic differences in hormone levels.

Resting pituitary levels of beta-endorphin-(beta-EP-IR), ACTH-(ACTH-IR), and alpha-MSH-(alpha-MSH-IR)-like immunoreactive material were found to differ among 16 inbred mouse strains. Hormone levels correlated genetically with severity of withdrawal from ethanol, which also differed among the strains. Ethanol dependence led to reduced pituitary beta-EP-IR in 4 of 5 strains studied. After 24 hr of withdrawal, 3 of those 4 showed elevated pituitary beta-EP-IR. These results are consistent with the hypothesis that genetically-determined difference in pituitary hormone functioning underlie some of the genetically-determined differences in ethanol withdrawal severity.

Adrenocorticotropic Hormone↗
PubMed1983

Genetic selection for ethanol withdrawal severity: differences in replicate mouse lines.

We report an ongoing within-family selective breeding project for the severity of handling-induced withdrawal seizures in mice made physically dependent on ethanol by inhalation. Two Withdrawal Seizure Prone (WSP) and two Withdrawal Seizure Resistant (WSR) lines have been subjected to five generations of selection, and two control (WSC) lines are maintained. Each WSP line had more severe and each WSR line had less severe withdrawal convulsions than its respective WSC line. Differences relative to control lines were more pronounced in the WSP lines and were not due to differences in effective dose of ethanol. Heritabilities were higher in the WSP lines than in the WSR lines. These lines will be useful for studying physiological determinants of ethanol dependence and withdrawal.

Animals↗
PubMed1983

Genetic correlations with ethanol withdrawal severity.

A major goal of pharmacogenetic research on alcoholism remains the identification of some "marker" that could predict the liability of a particular individual for a genetic susceptibility to develop alcoholism. The present paper presents evidence that the severity of withdrawal from physical dependence on ethanol varies widely among inbred strains of mice, and that withdrawal severity is negatively genetically correlated with initial sensitivity and magnitude of tolerance to ethanol hypothermia. These correlations are supported by differences in hypothermic response between replicate lines of mice genetically selected for susceptibility and resistance to ethanol withdrawal seizures. The genetic relationships reported suggest that the effects of ethanol on thermoregulation in mice may offer a predictive marker for susceptibility to ethanol physical dependence.

Alcohol Withdrawal Delirium↗
PubMed1982

Biphasic effects of ethanol on open-field activity: sensitivity and tolerance in C57BL/6N and DBA/2N mice.

Male C57BL/6N (C57) and DBA/2N (DBA) inbred mice were found to differ in open-field behavior after an acute ip injection of ethanol and in the development of tolerance to repeated injections. DBA mice showed only increased activity for 28 min after ethanol doses up to 2.67% g/kg when compared with saline-injected controls. Under the same conditions, C57 mice showed dose-related increases in activity during the first 4 min, followed by dose-related decreases in activity. The effects endured for at least 60 min after injection in both strains. In a third experiment, mice were injected daily with saline or 2.0 g/kg ethanol and tested on Days 1, 5, 9, and 13 for open-field activity. On the 17th day, all mice were tested after an ethanol injection. Neither strain showed tolerance to the activity-stimulating effect of ethanol. Some evidence for tolerance to the effect of ethanol to reduce activity in C57 mice was found. In a fourth experiment, twice-daily injections of ethanol for 10 days produced marked tolerance to the depressant effect of an injection on the 11th day in C57 mice, compared with those in a control group given ethanol for the first time on the 11th day. No tolerance to the stimulant effect of ethanol was seen in C57s. DBA mice were injected twice daily for 19 days but did not display tolerance when tested on Day 10 or on Day 20, Indeed, DBA mice chronically treated with ethanol exhibited more marked stimulation of activity after ethanol than mice treated chronically with saline. Differences in blood ethanol concentrations between the strains could not account for any of the observed differences. Implications for the genetic control of responses to ethanol are discussed.

Animals↗
PubMed1982

Tolerance to ethanol hypothermia in inbred mice: genotypic correlations with behavioral responses.

Hypothermia was studied 5 min before, and 30 and 60 min after intraperitoneal administration of ethanol (3 g/kg) in 20 inbred strains of mice. Ethanol was given daily for 8 days, and temperatures were taken on Days 1, 3, 5, and 8. Tolerance was indexed by the reduction in hypothermia over days. There were large strain differences in baseline temperature, the hypothermic effect of ethanol, and in development of tolerance to hypothermia. Some strains of mice (DBA/1J, DBA/2N, MA/MyJ, and PL/J) did not develop tolerance to the hypothermic effect of ethanol. Initial sensitivity to the hypothermic effect of ethanol was significantly genetically correlated with tolerance development, indicating control of these responses by common genes. Ethanol-induced changes in activity and ataxia, as well as blood ethanol concentrations, were also assessed. Although there were significant strain differences in activity reduction, ataxia, blood-ethanol concentrations, and changes in these parameters during the course of chronic treatment, none of these variables could explain the genetic differences in hypothermic sensitivity and tolerance.

Animals↗
PubMed1981

Strain differences in pituitary beta-endorphin and ACTH content in inbred mice.

The whole pituitary contents of beta-endorphin and ACTH were found to vary widely among 5 inbred strains of mice. beta-endorphin values were 2.5-fold different and ACTH values 1.5-fold. Strains low in beta-endorphin were also low in ACTH. The existence of genetic differences raises the possibility that there exist, or can be developed, strains with extremely low or high levels of these peptides that would aid research directed at elucidating the physiology of opioid peptides.

Adrenocorticotropic Hormone↗