Strain differences of ether susceptibility in mice

The susceptibility to ether in the following six strains of mice was tested: C57BL/6, DBA/2, BALB/c, C3H/He, ICR and ddY. Mice of 4 weeks old were exposed to a flow of air containing various concentrations of ether for 90 min and the mortalities were assessed. The C57BL/6 strain was the most resistant and the C3H/He strain was the most sensitive to the lethal effect of ether. The susceptibilities of the closed colony mice, ICR and ddY, were intermediate between those of C57BL/6 and C3H/He mice. The DBA/2 and BALB/c strains were more sensitive than these closed colony mice and made up a sensitive group with the C3H/He strain. The LD50 values for ether in male mice of C57BL/6 and C3H/He were 6.0 and 3.1% atm, and in female mice of these strains were 6.6 and 3.2% atm, respectively. The ED50 value of ether which was accompanied by loss of righting reflex after exposure for 10 min was also higher in male C57BL/6 mice than in male C3H/He mice.     

Strain differences of the ability to hydroxylate methotrexate in rats

Converting activity of methotrexate (MTX) to 7-hydroxymethotrexate (7-OH-MTX) was examined using eight strains of rats. Marked variability of the activity was found in liver cytosols from the rats. The highest activity was observed with Sea:SD rats, followed by LEW/Sea and Jcl:Wistar rats. The lowest activity was observed with WKA/Sea rats. The difference in the activity between Sea:SD and WKA/Sea strains was 104-fold. The variation was correlated to the strain difference of benzaldehyde oxidase activity in the rats. The cytosolic 7-hydroxylase activities in other tissues of Sea:SD rats were much higher than those of WKA/Sea, similarly to the case in liver. The liver microsomes of Sea:SD rats exhibited no 7-hydroxylase activity toward MTX even in the presence of NADPH. The cytosolic 7-hydroxylating activity of the livers of Sea:SD rats was inhibited by menadione, β-estradiol, chlorpromazine and disulfiram, inhibitors of aldehyde oxidase, but not oxypurinol, an inhibitor of xanthine oxidase. The purified aldehyde oxidase from the livers of Sea:SD rats exhibited a significant 7-hydroxylating activity toward MTX. However, xanthine oxidase had no ability to hydroxylate MTX. These facts suggest that MTX hydroxylating activity in rats is predominantly due to aldehyde oxidase, and the strain differences are due to the variations of the flavoenzyme level.     

Stock differences in the susceptibility of rats to learned helplessness training

Learned helplessness (LH) consists of shock escape deficits evidenced by animals previously exposed to inescapable shock. This phenomenon has shown promise as a behavioral screen for new antidepressant drugs. Unfortunately, some stocks of rats evidence low susceptibility to LH training. Accordingly, male rats from 8 different stocks were tested for susceptibility to LH training. The outbred stocks consisted of Harlan SD, Sasco Holtzman, and Charles River Holtzman. The inbred stocks (i.e. strains) tested were Lewis, Wistar Kyoto, Brown Norway, Fischer F-344, and Buffalo. The Lewis, Brown Norway, Fischer and Sasco Holtzman rats were found to be virtually non-susceptible to LH training. Harlan SD and Buffalo rats evidenced intermediate susceptibilities of 28% and 33%, respectively. Kyoto and Charles River Holtzman rats were the most susceptible at 53% and 55%, respectively. No stock differences between control animals were observed. These results indicate that wide differences in susceptibility to LH training exist in rats from different stocks or suppliers and researchers should be careful to choose subjects from a susceptible stock. Charles River Holtzman and Wistar Kyoto rats appear to be very susceptible to LH training.     

Strain differences in delay discounting using inbred rats

A heightened aversion to delayed rewards is associated with substance abuse and numerous other neuropsychiatric disorders. Many of these disorders are heritable, raising the possibility that delay aversion may also have a significant genetic or heritable component. To examine this possibility, we compared delay discounting in six inbred strains of rats (Brown Norway, Copenhagen, Lewis, Fischer, Noble and Wistar Furth) using the adjusting amount procedure, which provides a measure of the subjective value of delayed rewards. The subjective value of rewards decreased as the delay to receipt increased for all strains. However, a main effect of strain and a strain × delay interaction indicated that some strains were more sensitive to the imposition of delays than others. Fitting a hyperbolic discount equation showed significant strain differences in sensitivity to delay ( k ). These data indicate that there are significant strain differences in delay discounting. All strains strongly preferred the 10% sucrose solution (the reinforcer in the delay discounting task) over water and the amount of sucrose consumed was correlated with sensitivity to delay. Locomotor activity was not correlated with delay discounting behavior. Additional research will be required to disentangle genetic influences from maternal effects and to determine how these factors influence the underlying association between heightened delay discounting and neuropsychiatric disorders.     

Strain differences in teratogenic susceptibility to trypan blue between WM and BDIX rat strains

Female rats of WM (Wistar-Mishima)/Nem strain were mated with WM/Nem (group W) or BDIX/Nem males (group WB), and BDIX/Nem females were mated with BDIX/Nem (group B) or WM/Nem males (group BW). On day 8 of gestation, pregnant females were treated intraperitoneally with 1% aqueous solution of trypan blue at a dose of between 20 and 120 mg/kg of body weight. On day 20 of gestation, fetuses were examined for external, visceral, and skeletal malformations. In group W, fetal mortality increased dose dependently at doses higher than 20 mg/kg, and incidences of external, visceral, and skeletal malformations were significantly higher than control at doses of 30 mg/kg and more. In group B, fetal mortality and the incidence of external malformations were significantly higher than control only in the group treated with 120 mg/kg, and no significant increase of visceral and skeletal malformations was shown. It was confirmed that BDIX strain is much more resistant to trypan blue teratogenicity than WM strain. In group BW, nearly the same teratogenic effects were shown as in group W in terms of fetal mortality and incidence of malformations. However, in group WB, teratogenic effects were not so remarkable as in group BW, suggesting patroclinous effects in teratogenic susceptibility to trypan blue. In group BW, sex differences in teratogenic susceptibility were found; male fetuses were more susceptible to trypan blue than females.     

Strain differences regarding susceptibility to ursolic acid-induced interleukin-1beta release in murine macrophages

Interleukin (IL)-1beta is a proinflammatory cytokine responsible for the onset of a broad range of diseases, such as inflammatory bowel disease and rheumatoid arthritis. We have recently found that aggregated ursolic acid (UA), a triterpene carboxylic acid, is recognized by CD36 for generating reactive oxygen species (ROS) via NADPH oxidase (NOX) activation, thereby releasing IL-1beta protein from murine peritoneal macrophages (pMphi) in female ICR mice. In the present study, we investigated the ability of UA for inducing IL-1beta production in pMphi from 4 different strains of female mice (C57BL/6J, C3H/He, DDY, and ICR), as well as an established macrophage line (RAW264.7 cells). The levels of IL-1beta released from UA-treated pMphi of C57BL/6J and DDY mice were significantly lower than from those of ICR mice, whereas IL-1beta was not released from the pMphi of C3H/He mice or RAW264.7 cells. Of paramount importance, CD36 as well as the NOX components gp91phox and p47phox (C3H/He mice) and gp91phox (RAW264.7 cells) were scarcely detected. In addition, the different susceptibilities to UA-induced IL-1beta release were suggested to be correlated with the amount of superoxide anion (O2-) generated from the 5 different types of Mphi. Notably, intracellular, but not extracellular, O2- generation was indicated to play a major role in UA-induced IL-1beta release. Together, our results indicate that the UA-induced IL-1beta release was strain-dependent, and the expression status of CD36 and gp91phox is strongly associated with inducibility.     

Strain differences of hypertension induced by dietary NG-nitro-L-arginine in normotensive rats.

When the potent inhibitor of nitric oxide (NO) synthesis NG-nitro-L-arginine (L-NNA) was incorporated into the diet, hypertension was induced and sustained due to the effects of the long-term inhibition of endothelium-dependent relaxing factor (EDRF)/NO. The effects of L-NNA on normotensive rats of four strains (Donryu, Sprague-Dawley (SD), Wistar, and Wistar-Kyoto (WKY)) were compared relative to control rats. L-NNA administration caused a sharp initial increase in systolic blood pressure (SBP) at 2 weeks in all animals, and this was followed by a gradual and steady increase until 4 weeks. At the end of the experiments (5 weeks), the mean SBP of Donryu and SD rats was decreased. The maximum blood pressure of Donryu and Wistar rats during the experiments exceeded 200 mmHg, but that of SD and WKY rats was below 200 mmHg. Body weight loss and death were observed only in L-NNA-fed Donryu rats. Pathological changes in the kidneys and the morbidity rates for the lesions were determined, and indicated that the Donryu L-NNA group was 100% positive. These results suggest that the Donryu strain is more sensitive to L-NNA than the other strains. That dietary L-NNA-induced hypertension in normotensive rats of the four strains provides a new artificially-induced hypertensive model in which vasoconstriction occurs mainly due to EDRF deficiency.     

Strain differences in kidney copper concentrations of male rats

The copper concentrations of the kidneys of male rats of six inbred (BN, F344, LEW, SHR, WAG/Cpb, and WAG/Rij) and one random-bred Wistar strain were determined. In inbred rats the mean concentration varied between strains and ranged from 7.10 μg/g for F 344 to 23.48 μg/g for WAG/Cpb. The calculated coefficient of genetic determination (g²) was 0.88. A remarkable discrepancy was found between the two WAG inbred strains; the WAG/Cpb had a 2.5 times higher kidney Cu concentration than the WAG/Rij. Kidney Cu concentrations of random-bred rats varied considerably; the coefficient of variation of the means was 28 and 34% in two samples taken with a 1-yr interval, respectively, indicating inhomogeneity within the population. The results indicate that the individual differences in kidney Cu concentration have a genetic basis.     

Strain differences in avoidance reactions of septal laboratory rats

The effect of a lesion of the dorsal septum on active and passive type of avoidance reactions of adult male Wistar (W) and Long-Evans (LE) rats was studied. The rate of acquisition and extinction of the reaction was studied by 3 different testing methods. The animals were operated on when juvenile (30 days) or adult (90 days). The experiments were always started 50 days after the operation, when the "rage syndrome" was no longer present. In the three different tests we found a single common variable--the strain factor. It was this that determined whether the operation was effective, as well as the direction of deviations and the operation age which led to manifest changes. In W males the lesion did not impair either the acquisition or the extinction of an active avoidance reaction (AAR); the passive avoidance reaction (PAR) was acquired and extinguished more slowly after a lesion in adulthood. The spontaneous passive avoidance reaction (i.e. preference of a small, dark space) was likewise negatively affected by the operation. In intact LE animals the AAR was extinguished more slowly than in intact W males; after a lesion produced in juvenile or adult age extinction was speeded up, so that there were no differences compared either with intact or with septal W animals. Intact LE rats also acquired a PAR more slowly than W rats; a septal lesion led to faster acquisition, irrespective of the age at which the operation was performed, so that the rate for septal LE rats were the same as for intact W animals. The extinction of this reaction took longer after an operation at juvenile age and the rate for these septal LE rats were the same as for those of septal W individuals operated on at 90 days. The spontaneous PAR was qualitatively poorer in intact LE animals than in intact W rats, since only 40% of them preferred the small, dark space. A lesion was followed by improvement, which was especially marked after operation on the 30th day, when all the animals preferred this space, and in a very short time, so that they were equal to intact W males. Correlation of the acquisition and the extinction rate showed that there was imbalance of excitation and inhibition processes in the AAR of the W controls, that they were balanced in the PAR and that the lesion reversed these relationships. Both processes were balanced in the LE control and a septal lesion did not alter the situation.     

Strain and sex differences in the cardiopulmonary adaptation of rats to high altitude

On chronic exposure to hypoxia, the commercially available Hilltop (H) strain of male Sprague-Dawley rats develops severe pulmonary hypertension, right ventricular hypertrophy (RVH), and polycythemia. These signs of chronic mountain sickness are associated with a high mortality rate. In contrast, the Madison (M) strain of Sprague-Dawley rats remains healthy with significantly less severe cardiopulmonary and hematological responses. Breeding experiments under locally controlled conditions were undertaken to determine if the differences between the two strains were genetically determined and to look for possible sex differences. Following 30 to 50 days exposure to a simulated altitude of 18,000 ft, the first generation of male H rats exhibited a higher right ventricular peak systolic pressure (RVPP), a more pronounced RVH, and a greater degree of polycythemia than the male M rats. The H rats had a mortality rate of 40% in contrast to a rate of 0% in the male M rats. The first generation of female H rats also developed a higher RVPP, a greater RVH, and more severe polycythemia than that in the female M rats. There were no differences in RVPP or RVH between the males and females of either strain. Females of both strains tolerated the hypoxic exposure with a 0% mortality rate. The data suggest that the differences between the males of H and M strains in their cardiopulmonary and hematological responses and in their susceptibilities to chronic hypoxia are genetic in nature. They further suggest that the female resistance to hypoxia is not due to milder cardiopulmonary responses. Perhaps female rats tolerate RVH better than male rats, at least of the H strain.     

Strain differences in faecal tryptic activity of germ-free and conventional rats

Regardless of diet (semi-synthetic or lab chow) or strain (AGUS or SD), germ-free rats have tryptic activity in their faeces, whereas conventional rats never do. The activity in faeces from germ-free AGUS rats was significantly higher than from SD rats.     

Strain differences in response of Sprague-Dawley and Long Evans Hooded rats to the teratogen nitrofen

Administration of nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) during organogenesis in rodents produces neonatal lethality accompanied by lung hypoplasia, diaphragmatic hernias, heart anomalies, and hydronephrosis. Different strains of rats, Long Evans Hooded (LEH) and Sprague-Dawley (SD), are reported to have different malformation responses to prenatal exposure, which could be due to true strain differences, to different levels and times of exposure, or to the use of different methods for detecting visceral malformations. In the present study, LEH, SD, and "virus-antibody-negative" SD (VAN-SD) rats were identically exposed to 0, 6.25, 12.5, or 25 mg/kg/day of nitrofen by gavage in corn oil on days 6 15 of gestation. At term, half of the litter was examined by the Wilson method of razorblade sectioning and the remainder by a modified Staples method of fresh visceral examination. The two methods were equally sensitive for detecting diaphragm, kidney, and lung anomalies, whereas heart malformations were more frequently identified with fresh visceral examination. The frequency of total malformations did not vary across strains at any dose, but there were substantial differences in the pattern of malformations in each strain. SD and VAN-SD rats responded similarly for all malformations, but had significantly higher incidences of diaphragm and lung anomalies than LEH rats. Conversely, LEH rats had significantly elevated levels of kidney anomalies compared to SD and VAN-SD rats, whereas frequency of heart malformations was low and comparable across strains. These results suggest that true strain differences exist in the pattern of malformation produced by prenatal exposure to nitrofen that may be based on genetic differences in embryonic susceptibility.