Ethanol preference in Maudsley and RXNRA recombinant inbred strains of rats.
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Alcohol Drinking↗
Biomedical subjects
D A Blizard
Publications and source records attributed to D A Blizard.
Association between ethanol and sucrose intake in the laboratory mouse: exploration via congenic strains and conditioned taste aversion.
BACKGROUND: A substantial body of literature indicates that intakes of "sweet" solutions and ethanol are positively correlated across inbred strains of rats and mice but there has been speculation that the correlation is fortuitous and there is no agreement on the underlying mechanism. METHODS AND RESULTS: We assessed the correlation between intake of sucrose and ethanol in congenic mice created by backcrossing alleles favoring sucrose intake from the BXD RI-5 strain into DBA/2J. In addition, to probe more specifically the interrelationship between intake of the two solutions, we examined aversion generalization from sucrose to ethanol in C57BL/6J mice. Among the congenic mice, a statistically significant product-moment correlation of r = 0.36 (p < 0.02) was found between 6-hr intake of sucrose corrected for differences in baseline water intake and preference for 10% ethanol presented in a 96-hr 2-bottle test. Furthermore, C57BL/6J male mice conditioned to avoid a 0.2 M sucrose solution generalized their aversion to a 10% ethanol solution presented in the same 2-bottle test, drinking 42.1 +/- 9.38% (mean +/- SE) of their total fluid intake from the ethanol tube, compared with the control group mean of 69.86 +/- 8.84%. CONCLUSIONS: The positive association between intake of sucrose and ethanol in congenic mice provides strong evidence that the previously demonstrated genetic correlation between intake of these solutions is not the result of fortuitous fixation of unrelated alleles and provides suggestive evidence that, at least in the B6/D2 lineage, the genetic association between intakes of the two solutions reflects close linkage or the pleiotropic effects of the same genes. The demonstration that a conditioned taste aversion to sucrose generalized to ethanol in the C57BL/6J inbred mouse strain is an extension of similar observations in outbred rats and specifically demonstrates that intake of the two solutions is controlled by some of the same physiologic or neurological processes and thus is consistent with the pleiotropic interpretation of the genetic correlation.
Alcohol Drinking↗
Chorda tympani responses in two inbred strains of mice with different taste preferences.
Behavioral studies suggest that there are significant differences in the taste systems of the inbred mouse (Mus musculus) strains: C57BL/6J (B6) and DBA/2J (D2). In an attempt to understand the biological basis of the behavioral differences, we recorded whole-nerve chorda tympani responses to taste solutions and compared the results to intake of similar solutions in nondeprived mice. Stimuli included a test series composed of 0.1 M sodium chloride, 0.3 M sucrose, 10 mM sodium saccharin, 3 mM hydrochloric acid, and 3 mM quinine hydrochloride, as well as concentration series for the same substances. Neural activity of the chorda tympani that was evoked by sucrose, saccharin, or NaCl was greater in B6 than D2 mice; and neural threshold for sucrose was lower in B6 mice, but neural thresholds for HCl and quinine were lower in D2 mice. B6 mice drank more sucrose and saccharin but less quinine than D2 mice; thus, sucrose and saccharin preference were positively correlated, but NaCl and quinine aversiveness were negatively correlated with the chorda tympani results. Nonetheless, genes involved in the structuring of taste receptors and/or the chordae tympani, which transduce taste stimuli having diverse perceptual qualities, differ for the two mouse strains.
Analysis of Variance↗
Quantitative trait loci associated with short-term intake of sucrose, saccharin and quinine solutions in laboratory mice.
The goal of this study was simultaneously to map two genetic loci which, collectively, have a large effect on intake of sucrose, saccharin and quinine solutions in mice. These loci had been previously identified using long-term measurements with the traditional two-bottle test, but the present study used a short-term, one-bottle test. Intake of distilled water, 100 mM sucrose, 10 mM sodium saccharin and 1.1 mM quinine HCl over 6 h was measured on two occasions from a non-deprived group of 61 male and 72 female F2 mice derived from a cross of the C57BL/6J and DBA/2J mouse strains and used to detect quantitative trait loci (QTL). DNA from each animal was typed for polymorphisms in anonymous microsatellite markers on mouse chromosomes 4 and 6. Saccharin and sucrose relevant QTL were detected on distal chromosome 4 and a quinine relevant QTL was detected on medial/distal chromosome 6 in the region of Prp. The location of these QTL and the proportion of phenotypic variance they accounted for were similar to those arrived at following previous determinations using the two-bottle test. Measurement stability for the three gustatory phenotypes was high, product-moment correlation coefficients between first and second determinations varying between approximately 0.80 for sucrose and saccharin and 0.73 for quinine. QTL parameters assessed independently for first and second presentations of sucrose and saccharin were stable, but the location of the quinine QTL differed between presentations. The present experiment illustrates the utility of a 6 h fluid intake test in the mapping of Sac and Qui loci. The short duration of the test provides a simple means of measuring variation in gustatory processes and the discovery that these loci influence short-term as well as long-term fluid intake extends understanding of the mechanism of gene action.
Analysis of Variance↗
Measuring gustatory variation in mice: a short-term fluid-intake test.
A short-term fluid-intake test is described which is directed at the study of individual variation in gustation in laboratory mice. To avoid position preferences associated with two-bottle tests, single graduated cylinders are used to present the solution. Intake of water and solutions is recorded for a 6-h period beginning 3 h prior to the dark phase of the light cycle. The timing of data collection ensures a stable baseline of fluid intake because it coincides with the period in which mice begin to drink. Food and water are available ad lib. at all other times so the test avoids the water restriction that is often used in gustatory studies. We report normative data on ten commonly used inbred strains for sucrose (100 mM), saccharin (10 mM), quinine (1.1 mM), HCI (1 and 3 mM). NaCl (320 mM), and monosodium glutamate (150 mM). Strain differences were pronounced for all tastants. Concurrent measures of food and fluid intake by C57BL/6J and DBA/2J mice demonstrated that the short-term reduction of fluid intake resulting from 6-h quinine administration, which was restricted to C57BL/6J mice, was associated with a minor reduction in food intake during the 6-h test and had no statistically significant effect on food or fluid intake during the 18-h post-test period or during a 6-h period the next day. The absence of large-scale or persistent nonspecific effects supports the use of the paradigm for screening of multiple solutions on the same animals. The reliability of the test is supported by positive correlations between repeated measurements of the same solution across substantial time intervals. Its ease of use, substantial reliability, and avoidance of water restriction make the test a very useful addition to screening tools in the field of gustation research.
Analysis of Variance↗
Ethanol consumption in rats selectively bred for differential saccharin intake.
Rat lines selectively bred for high ethanol consumption consume more saccharin solution than do their low-ethanol-consuming counterparts. The present study utilized the technique of reciprocal selection to examine the reliability of the saccharin/ethanol relationship; specifically, consumption of 1-10% ethanol solution was measured in rats selectively bred for high vs. low saccharin consumption (Occidental HiS and LoS lines). HiS rats consumed more ethanol than did LoS rats. These results support the idea that individual differences in ethanol and saccharin consumption share some common mechanism(s).
Animals↗
Alcohol acceptance, preference, and sensitivity in mice. II. Quantitative trait loci mapping analysis using BXD recombinant inbred strains.
Quantitative trait loci (QTL) mapping of complex phenotypes has emerged as an important feature of the recombinant inbred (RI) strain methodology. In this second study of our series on alcohol-related behaviors in mice, we examine alcohol acceptance, preference, and hypnotic dose sensitivity (HDS) to a standard dose of alcohol measured in BXD RI strains to identify candidate QTL regions responsible for their heritability. We detected highly significant marker associations for acceptance on chromosome 12 (Eif4e), for preference on chromosome 1 (D1Rti2) and chromosome 7 (D7Mit7), and for HDS on chromosome 7 (Mpmv1). These are the strongest QTL associations that we detected, but several other candidate QTL regions are reported. Given the limited number of BXD RI strains available, the large number of markers used herein, and the consequent chance of identifying false marker associations, these RI QTL mapping results must be seen as tentative, but an important first step toward identifying QTL for alcohol-related behaviors.
Alcohol Drinking↗
The Maudsley rat strains as a probe to investigate noradrenergic-cholinergic interaction in cognitive function.
Central noradrenergic function in relation to cognitive performance was studied in the Maudsley rat strains. Neurochemical studies revealed a higher response to acute stress in the locus coeruleus (LC) in the Maudsley reactives (MR) than in the Maudsley non-reactives (MNRA). Autoradiographic studies showed that MNRAs had greater 125I clonidine binding to alpha 2 receptors in LC, which was accompanied by a higher behavioral sensitivity to clonidine. MRs had a deficit in working memory, but were superior to MNRAs in two reference memory tasks. MRs displayed a stronger preference for novel objects, with no strain differences in general exploratory activity. The behavioral profile of the MRs is similar to rats treated with drugs which enhance noradrenergic function. Furthermore, MNRA rats had greater availability of muscarinic receptors, which correlated with behavioral performance in the spatial working memory task. The differences in noradrenergic and cholinergic systems and their relationship to the behavioral profile make the Maudsley strains a useful tool to probe the interaction between two neurotransmitter systems in cognitive function.
Age Factors↗
Alcohol acceptance, preference, and sensitivity in mice. I. Quantitative genetic analysis using BXD recombinant inbred strains.
Although the recombinant inbred strain method was designed for molecular genetic analysis of linkage, it also provides powerful quantitative genetic analyses of heritability and genetic correlations. Measures of alcohol acceptance, alcohol preference, and hypnotic dose sensitivity (HDS) were assessed in 21 strains of mice from the BXD RI series. Sex differences were found to be significant at a phenotypic level. However, heritability estimates for acceptance, preference, and HDS are similar in males and females. Heritability estimates for the three measures are approximately 0.20 for acceptance and preference, and 0.10 for HDS. Analyses of genetic correlations reveal that acceptance and preference share some degree of genetic influence, although they mostly operate under different genetically mediated mechanisms. HDS did not show a significant genetic relationship to either acceptance or preference. Strong correlations were obtained when acceptance, preference, and HDS strain means were correlated across male and female recombinant inbreds, suggesting substantial genetic similarity across sexes.
Alcohol Drinking↗
The utilization of quantitative trait loci in toxicogenetics.
With the increasing number of marker loci available in mouse, the traditional method of recombinant inbred strains can be extended to searches for quantitative trait loci (QTL) influencing continuously distributed phenotypes. These loci have effect sizes too small to be easily detectable by conventional single-locus techniques. Collective, several QTL may account for a substantial proportion of the phenotypic variability. Prospective advantages of location of QTL in toxicology-relevant phenotypes include opportunities for the study of mechanism, prospects of generating animal models by genotypic selection, study of the dynamics of gene interaction, and guiding the search for homologous genes in human beings.
Alleles↗
Maternal influences on cardiovascular pathophysiology.
Elevated blood pressure (BP) is of special clinical significance because of its association with pathophysiologies such as heart disease, renal failure, and stroke. We described the development of a protocol for use with hypertensive rats in which prepubertal exposure to a high salt (8% NaCl) diet results in a pathophysiological syndrome including rapid increase in BP, failure to maintain normal weight gain, renal damage, cerebrovascular lesions, and early mortality. These phenomena are described for the inbred spontaneously hypertensive rat (SHR), and for reciprocal F1 hybrids of a cross between SHR and the Dahl salt-sensitive (SS/Jr) inbred strain. The study with reciprocal F1s revealed striking effects of maternal environment on pathophysiological response to a high salt diet. F1s nurtured by SHR mothers weighed less at 35 days of age, and after exposure to the high salt diet suffered more rapid BP increases, greater incidence of stroke, body weight loss, and mortality, than F1s nurtured by SS/Jr dams. These results suggest that maternal mediation of the nutritional status of the animal may play an important role in determining susceptibility to elevated BP and subsequent pathophysiology associated with exposure to a high salt diet. The implication of these findings for human hypertension is briefly discussed.
Animals↗
Recombinant-inbred strains: application to behavioral phenomena.
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Animals↗
Recombinant-inbred strains: general methodological considerations relevant to the study of complex characters.
If appropriately determined, recombinant-inbred (RI) strain means provide an excellent method for determining genetic correlations among complex characters. However, little systematic attention has been paid to important environmental influences on strain means such as random effects due to litter membership or systematic maternal influences, which are inevitably confounded with genetic effects. It is suggested that users of RI strains would do well to control for litter effects by sampling appropriately from many litters and assessing the potential role of maternal influences by appropriate fostering procedures. Concern for these and other environmental sources of variation has caused reliability of strain means to emerge as an important issue in studies with RIs which focus on complex characters. Examples of estimating the reliability of RI strain means are provided to draw attention to the value of this kind of information in both gene-mapping studies and genetic correlational analyses. In addition, particularly in the case of behavioral tests which are susceptible to considerable day-to-day variation, repeated testing of the same animals can serve to diminish the influence of extreme deviations which are due to random variations in the manner in which the test is conducted on any given day. The advantages of RIs for gene mapping are well established. However, via the power of genetic correlational analysis, the RI methodology is emerging as a major alternative method, e.g., as distinct from lesion studies, pharmacological interventions, etc., in the bio-behavioral sciences to explore relationships between different domains of inquiry. Via its cumulative and integrative power, it is likely to make a major contribution to investigations of relationships between complex characters at various levels of and this application which should be considered separately from its application to gene mapping.
Animals↗
Analyzing phenotypic correlations in studies with selected lines.
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Alcohol Drinking↗
Genetic and maternal influences in rat models of spontaneous and salt-induced hypertension.
Genetic and maternal influences on hypertension were studied by comparing the SHR and SS/Jr inbred rat strains and their reciprocal F1 hybrids under identical conditions. When raised on a low salt (LS) diet (0.3% NaCl), SHR rats had higher systolic blood pressure (SBP) than SS/Jr rats by 9 weeks of age. Direct recordings from freely moving rats at 18-24 weeks confirmed this difference. Placement on a high salt (HS) diet (8% NaCl) at 5 weeks of age significantly increased SBP within 3 weeks in all groups, although the degree of increment was significantly smaller in SHR females. Inbred strains had higher SBP than their F1 hybrids when measured indirectly and directly from arterial cannulae. After exposure to HS diet, F1 females reared by SHR dams exhibited larger increments in SBP, greater weight loss, and greater debilitation and associated mortality than F1 females reared by SS/Jr dams. Differences between inbred strains and F1s maintained on LS diet were consistent with dominance for low BP, and differential genetic control of hypertension in each inbred strain. F1 differences demonstrated that maternal factors affected body weight in weanlings, pressor response to HS diet, and associated debilitation.
Animals↗
Circadian rhythms of heart rate and mean arterial pressure in chronically instrumented pregnant rats.
With the use of a chronic preparation to directly monitor blood pressure and heart rate in pregnant rats, continuous data were obtained over the last half of gestation in normotensive rats. Over this time span, the animals showed significant decreases in blood pressure and increases in heart rate. Heart rate exhibited marked and consistent circadian rhythmicity with peaks occurring near the midportion of the dark phase of the 24-hour cycle. Blood pressure rhythms were less prominent and peaked later. The trends observed in blood pressure and heart rate over gestation suggest that the pregnant rat is a useful model for studying the cardiovascular effects of pregnancy.
Animals↗
Ethanol preference in the Harrington derivation of the Maudsley Reactive and Non-Reactive strains.
Ethanol intake was explored in the Harrington derivation of the Maudsley Reactive and Maudsley Non-Reactive rat strains (MR/Har and MNRA/Har). When 5% and 10% ethanol solutions were presented as the sole source of fluid (1-bottle test), MR/Har rats, respectively, ingested 15% more, or 9% less, than their baseline water intake, whereas MNRAs ingested 6% less, or 42% less than their baseline intake. However, because MNRA/Har rats drank significantly more water than MR/Har's under ad libitum conditions (MNRA/Har, 46.6 +/- 1.83 ml; MR/Har 32.45 +/- 1.64 ml/24 hr), males and females of the two strains ingested a similar amount of ethanol in the 1-bottle test (5% ethanol, 4-7; 10% ethanol, 6-12 g/kg body weight/24 hr). In 2-bottle free-choice tests administered after an extended period of forced ethanol consumption, MR/Har male and female rats exhibited a strong ethanol preference (X = 80%) and consumed a larger amount of ethanol (MR/Har, 7-13; MNRA/Har, 6-9 g/kg body weight/24 hr) than MNRA/Har's. Across all conditions, females of both strains ingested a greater relative amount of ethanol than males. The strain difference in ethanol preference was found to be independent of prior exposure to ethanol because it was also found when 2-bottle free-choice tests were carried out in naive animals (Experiment 2). The pattern of development of ethanol preference in individual animals was characterized by abrupt onset, after variable periods of exposure to the 2-bottle choice test, and maintenance of strong ethanol preference thereafter. The extensive behavioral and biological definition of the Maudsley strains is a valuable asset in attempting to elucidate the biobehavioral correlates of ethanol preference.
Alcohol Drinking↗
The effect of a high salt diet and gender on blood pressure, urinary protein excretion and renal pathology in SHR rats.
A high salt diet produced increases in SBP, urinary protein excretion (UPE) and renal vascular lesions (RVL) across groups of male and female SHR rats which were allowed to develop moderate or excessive increases in SBP. A highly significant linear relationship between SBP and log-transformed UPE was found when the data from all groups were analyzed together. Males developed high blood-pressure more rapidly, and exhibited more severe RVL and greater UPE than females. Two results prevent the conclusion that the elevated UPE was simply due to the adverse effects of high BP on the kidney. First, the relationship between SBP and UPE across groups could not be demonstrated when regression analyses were performed within individual dietary sub-groups. Secondly, gender differences in UPE were highly significant by analysis of covariance adjusting for individual differences in SBP. The increases in SBP and UPE may be independent consequences of ingestion of a high salt diet.
Animals↗