[A closed colony of laboratory rats].
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Animal Husbandry↗
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Confounding factors in toxicity testing.
The necessity for understanding normal human functions and the mechanisms which underlie dysfunction in these processes is essential in the promotion of a healthier lifestyle. To achieve this goal utilization of a suitable animal model is necessary in order to develop new pharmaceutical agents to alleviate diseases or chemicals to enhance the quality of life. It is incumbent upon investigators to choose a species in which pharmacokinetic principles are established and it is important that these phenomena resemble those of the humans. The choice of rats has specific advantages in that these rodents possess similar pharmacodynamic parameters to humans. Other advantages include availability, low cost, ease of breeding, and an extensive literature data-base to enable comparisons to present findings. However, in the interpretation of data from animals to humans, there are factors which need to be recognized as playing important roles in chemical-induced outcomes. The confounding factors include strain, supplier, age, gender, hormonal status and dietary intake. The aim of this article is to demonstrate that there are differences in the responsiveness of rat stock/strains to chemicals and that lack of consideration of confounding factors yields inappropriate conclusions regarding risk assessment for humans.
Age Factors↗
Comparison of arterial blood pressure in different strains of mice.
The present study was performed to compare the resting level of arterial blood pressure when monitored for 24 h/day in outbred Swiss Webster (SW) and inbred C57BL/ 6J, A/J, C3HeB/FeJ, and SWR/J mice. Mean arterial pressure (MAP) and heart rate (HR) varied throughout the day, with maximal values observed in the hours of darkness. Systolic (SAP), MAP, and diastolic (DAP) arterial blood pressure averaged 122 +/- 2, 112 +/- 2, and 102 +/- 2 mm Hg, respectively, in conscious SW mice (N = 6). No differences were detected in the 24-h averages of MAP between SW, C57BL/6J (N = 7), A/J (N = 5), C3HeB/FeJ (N = 5), or SWR/J (N = 7) mice maintained on a normal sodium diet. Average daily heart rate (HR) was highest in the C3HeB/FeJ (665 +/- 15 beats/min) and lowest in the C57BL/6J (594 +/- 9 beats/min). The MAP was significantly increased in SW mice administered L-NAME (133 +/- 2 mm Hg, N = 5) and significantly decreased in SW mice administered captopril (99 +/- 2 mm Hg, N = 5). These studies demonstrate similar levels of resting arterial pressure in different mouse strains under baseline conditions.
Animals↗
Inflammatory lesion and parasite load are inversely associated in Leishmania amazonensis infected mice genetically selected according to oral tolerance susceptibility.
Two strains of mice selected according to extreme phenotypes of susceptibility and resistance to oral tolerance (TS and TR mice, respectively) were infected with 1 x 10(7) Leishmania amazonensis promastigotes and studied comparatively. TS mice developed a minor pathology while permitting parasite growth with the presence of increased IL-4, IL-10 and IFN-gamma, and lower NO and IL-2 levels and delayed-type hypersensitivity (DTH). In contrast, in TR mice, footpad swelling was increased but parasite growth was reduced. They produced lower IL-4, IL-10 and IFN-gamma but increased NO, IL-2 levels, DTH, activated spleen macrophages and periarteriolar lymphoid sheaths. The results suggest that the tolerogenic TS mouse profile, with higher IL-10 production, impaired lesion development but also avoided macrophage leishmanicidal activity, maintaining in this manner a silent parasite load. On the other hand, the TR mouse profile contributed to lesion progression with controlled parasite load. To directly address the influence of oral tolerance on infection, mice were gavaged with OVA, and 7 days afterwards were infected and challenged to bystander suppression with OVA in the same footpad. In TR mice gavaged with 25 mg OVA the inflammatory lesion was largely enhanced, while with 5 mg OVA the lesion was diminished. In TS mice the footpad swelling was always lower. However, the bystander effect did not modify the establishment of infection; and similarly to the control non-bystander mice, parasite clearance was maintained in TR and prevented in TS mice. Therefore, a better comprehension of immunoregulation of innate and adaptive immunity in the early stages of infection is necessary for the development of protocols preventing inflammation and contributing to the elimination of parasites.
Administration, Oral↗
Differences in brain area concentrations of dopamine and serotonin in Myers' High Ethanol Preferring (mHEP) and outbred rats.
Both male and female mHEP rats consume excessive amounts of ethanol and thus offer a rational model for examining biochemical and behavioral differences with non-drinking rat lines. Differences in basal concentrations of 5-hydroxytryptamine (5-HT) and dopamine (DA) correlate with the consumption of ethanol in some ethanol-preferring rat lines. The concentrations of 5-HT and DA were examined by HPLC in five brain areas (prefrontal cortex, hippocampus, nucleus accumbens, striatum and hypothalamus) of ethanol-näive rats and after the oral administration of 0.25 or 1.0 g ethanol/kg in the male and female mHEP rat, the male Wistar rat, and the female Sprague-Dawley rat. The mHEP and control rats that received ethanol were screened for drinking in a 10-day "step-up" 3% to 30% ethanol solutions beginning at postnatal days 40 and 80, and then tested at 150 days of age. The levels of DOPAC in females were lower in the hippocampus of both naïve mHEP and ethanol-treated Sprague-Dawley rats. In striatum, the concentrations of 5-HT and DA were elevated in both mHEP and ethanol-treated Sprague-Dawley female rats. The concentrations of 5-HT and its metabolite, 5-HIAA, were lower in the nucleus accumbens of the ethanol-näive female mHEP rat relative to the female outbred control. In the male rats, the levels of DA, HVA and DOPAC, as well as 5-HT and 5-HIAA were reduced in the hypothalamus of both ethanol-näive mHEP rats and Wistar rats receiving ethanol by gavage. These data demonstrate differences in neurotransmitter activity between the selectively bred mHEP rat and the outbred rat strains. There are few common features found in both the male and the female mHEP rat when compared to their respective controls. Differences in neurotransmitter function in these brain areas may account for some of the behavioral differences previously demonstrated between the two sexes of the mHEP rat.
Alcohol-Induced Disorders, Nervous System↗
Differential sensitivity to acute administration of Ritalin, apomorphine, SCH 23390, but not raclopride in mice selectively bred for hyperactive wheel-running behavior.
RATIONALE: Previous studies of mice ( Mus domesticus) selectively bred for high voluntary wheel running have suggested that the hyperactivity is associated with dysfunction in the dopaminergic neuromodulatory system and that high-running mice may represent a useful genetic model for attention deficit hyperactivity disorder (ADHD). OBJECTIVES: We tested the hypothesis that mice from the four replicate hyperactive lines would respond differently to methylphenidate (Ritalin), apomorphine (non-selective dopamine agonist), SCH 23390 (selective D1-like dopamine antagonist), and raclopride (selective D2-like dopamine antagonist) than individuals from the four replicate, randomly bred, control lines. METHODS: After animals were habituated (3 weeks) to their cages with attached wheels, drugs were administered via intraperitoneal injections, at night, during peak wheel-running activity. Revolutions on wheels 10-70 min post-injection were used to quantify drug responses. RESULTS: Ritalin (15 mg/kg and 30 mg/kg) increased wheel running in control lines but decreased running in selected lines. A low-dose (0.125 mg/kg) of apomorphine reduced wheel running by a similar amount in control and selected lines; however, higher doses of apomorphine (0.25 mg/kg and 0.5 mg/kg) produced greater reductions in wheel running in the control lines. SCH 23390 (0.025, 0.05, and 0.1 mg/kg) caused greater reductions in wheel running in control than in selected lines. Raclopride (0.5, 1, and 2 mg/kg) reduced wheel running by a similar amount in control and selected lines. CONCLUSIONS: These results support the interpretation that genetically determined hyperactive wheel-running behavior is associated with altered dopaminergic function in this mouse model. More specifically, results suggest that D1-like (D1 or D5), but not D2-like (D2, D3, or D4), dopamine receptors have reduced function in the high-running mice. The fact that Ritalin decreased wheel running in selected lines further supports their use as an animal model of ADHD.
Animals↗
Prevention of thrombus formation with glyprolines on various models of prethrombotic state and thrombosis in rats.
Peroral administration of peptide Pro-Gly-Pro to 10-11-month-old rats with modeled prethrombotic state normalized functions of the anticoagulation system and produced a potent antiplatelet effect. Peroral administration of Pro-Gly peptide before provocation of thrombin generation and thrombus formation prevented death of animals from thrombosis. Experiments on rats with venous thrombosis induced by stasis and administration of thrombin showed that pretreatment with Pro-Gly peptide decreased the weight of formed thrombi.
Administration, Oral↗
Development and characterization of a novel, graded model of clip compressive spinal cord injury in the mouse: Part 2. Quantitative neuroanatomical assessment and analysis of the relationships between axonal tracts, residual tissue, and locomotor recovery.
A detailed examination of the histopathological features of the clip compression injury in mice was performed to understand the relationships between neurological function and existing pathology of the spinal cord. Adult, female CD1 mice underwent three grades of extradural clip compression injury (3-g, 8-g, and 24-g FEJOTA mouse clips), transection, and sham injury at T3-4. Quantitative behavioural assessments were performed for 4 weeks following SCI. After 4 weeks, Fluoro-Gold was introduced caudal to the SCI site, at T9, and was retrogradely transported for 5 days to the origin of spared axons through the injury site. Counts of retrogradely labeled neurons in the brain-stem, midbrain, and sensory-motor cortex indicated that the number of intact descending axons that traversed the lesion decreased with increasing injury severity (F > 28; df = 4; p < 0.0001; one-way ANOVA). Independent linear correlation analyses were performed between indices of neurological recovery (BBB and IP test), counts of retrogradely labeled neurons and morphometric assessments of normal residual tissue at the injury epicenter. The BBB test correlated strongly with the amount of residual tissue at the injury epicenter (R = 0.945, df = 28, p < 0.0001). Counts of neurons retrogradely labeled with Fluoro-Gold were also strongly correlated with the BBB scores. The extrapyramidal (raphespinal, reticulospinal, vestibulospinal, and rubrospinal) tracts had Pearson correlation coefficients (R) of 0.814, 0.812, 0.813, and 0.747, respectively (df = 28, p < 0.0001). The pyramidal (corticospinal) tract had a correlation of R = 0.747, df = 28, p < 0.0001 with the BBB scores. The IP scores also correlated strongly with the persistence of extrapyramidal (raphespinal, reticulospinal, vestibulospinal and rubrospinal) tracts with correlation coefficients of 0.801, 0.782, 0.790, and 0.836, respectively (df = 28, p < 0.0001). These data indicate that the counts of retrogradely labeled neurons at the origin of distinct descending motor pathways are predictors of the variance of the functional recovery measured by the BBB and IP tests following spinal cord injury. In addition, we provide a detailed neuroanatomical study of clip compression injury in mice that can be used to study the molecular mechanisms of SCI in knockout and transgenic mice.
Animals↗
Simultaneous orthotopic transplantation of carotid and aorta in the rat by the sleeve technique.
Graft vascular disease (GVD) remains the major limitation to long-term survival after solid organ transplantation. Aortic or carotid allografts in rats have been shown to be useful models because similar changes to those observed in man develop within weeks. Both immunological and non-immunological factors influence the process of GVD and a method that could permit rapid multiple arterial allotransplantation in the rat would be of great value. We performed simultaneous orthotopic aortic and carotid allotransplantations in 25 rats. The vessels were anastomosed using a sleeve technique. No immunosuppression was given. The animals were killed at 15, 30, or 60 days and histological analyses of the grafts were performed. The overall survival rate was 80% and the incidence of technical failure was very low. The histopathological aspect revealed typical progressive GVD. In conclusion, we have developed a new model of simultaneous aortic and carotid transplantation in rats. This model, which incorporates a modification of the sleeve anastomosis, is rapid and yields an easy tool to investigate immunological and non-immunological processes driving GVD.
Anastomosis, Surgical↗
[A trial of the preparation Cheblin-SK-1 in models of nematodiases].
A kerosene milky-stage walnut (Juglans spp.) extract, a folk medication, has come into wide use in the past 30 years. The drug CK-I was prepared on a scientific basis. Its acute toxicity and toxicological profile were studied on albino mice and rats, chickens, chicken embryos, piglets. The maximum non-lethal dose of CK-I was 19 g/kg for albino mice and 21 g/kg for albino rats. The drug can be classified as i.v. hazard class. The anthelmintic effects of CK-I were examined in mice with cyphaciasis and in chickens with ascariasis and heterakiasis. In murine cyphaciasis, CK-I given in a dose of 75 mg/kg to albino mice provided 100% efficiency. Its doses of 800 and 1000 mg/kg were required to achieve this effect in chick ascariasis and heterakiasis, respectively.
Animals↗
[The functional-morphological characteristics of alcohol-induced pathology as dependent on the nature of the intoxication and its nootropil correction in an experiment].
The response of hematological system, carbohydrate metabolism and pathomorphologic alterations in the viscera were studied for four weeks on the model of chronic alcoholization in conditions of hydrolytic alcohol production. It is shown that maximal deviations of all the parameters in white conventional rats occur after receiving a combined ethanol dose in inhalation of a mixture of methanol and furfurol vapour. Less manifest pathology was revealed in simultaneous introduction of nootropil solution. Thus, functional-morphologic changes in alcoholic intoxication in unfavourable environment are reversible in purposeful application of drugs with neurometabolic effect.
Alcoholism↗
Individual differences in the expression of a "general" learning ability in mice.
Human performance on diverse tests of intellect are impacted by a "general" regulatory factor that accounts for up to 50% of the variance between individuals on intelligence tests. Neurobiological determinants of general cognitive abilities are essentially unknown, owing in part to the paucity of animal research wherein neurobiological analyses are possible. We report a methodology with which we have assessed individual differences in the general learning abilities of laboratory mice. Abilities of mice on tests of associative fear conditioning, operant avoidance, path integration, discrimination, and spatial navigation were assessed. Tasks were designed so that each made unique sensory, motor, motivational, and information processing demands on the animals. A sample of 56 genetically diverse outbred mice (CD-1) was used to assess individuals' acquisition on each task. Indicative of a common source of variance, positive correlations were found between individuals' performance on all tasks. When tested on multiple test batteries, the overall performance ranks of individuals were found to be highly reliable and were "normally" distributed. Factor analysis of learning performance variables determined that a single factor accounted for 38% of the total variance across animals. Animals' levels of native activity and body weights accounted for little of the variability in learning, although animals' propensity for exploration loaded strongly (and was positively correlated) with learning abilities. These results indicate that diverse learning abilities of laboratory mice are influenced by a common source of variance and, moreover, that the general learning abilities of individual mice can be specified relative to a sample of peers.
Animals↗
[Stress-induced alteration of the antiaggressive effect of anxiolytics].
The influence of stresses of various etiology (prolonged isolation, inescapable electrostimulation) on the antiaggressive effect of anxiolytics was studied in outbread white male rats. It was established that, in contrast to the anticonflict effect (decreasing under the action of stress), then antiaggressive action of the drugs studied (diazepam, phenazepam, clonazepam, alprazolam) exhibits qualitative changes. In the absence of stress, the threshold of aggressive reaction is low and anxiolytics increase this level. Under the action of stress, the threshold of aggressive reaction increases, and the same drugs reduce this threshold to the normal level, thus producing proaggressive action. The degree of changes and the rate of restoration of the initial activity depend on the efficacy of anxiolytics, the strength and duration of stress, and on the duration of drug administration during the stress aftereffect. A possible mechanism of this phenomenon can be the interaction of the GABA-benzodiazepine and opiate endogenous systems.
Aggression↗
Ultrastructural changes in the optic nerves of rodents with experimental Creutzfeldt-Jakob Disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS) or scrapie.
This report describes the ultrastructural changes in the optic nerves of (1) hamsters infected with the Echigo-1 strain of Creutzfeldt-Jakob disease (CJD), (2) hamsters infected with the 263K or 22C-H strain of scrapie, and (3) mice infected with the Fujisaki strain of Gerstmann-Sträussler-Scheinker disease (GSS). Vacuolation of myelinated fibres was present in the myelin sheaths, with splitting of myelin lamellae. These vacuoles contained typical secondary vacuoles and curled membrane fragments. Myelinated fibre vacuolation was also accompanied by an exuberant cellular reaction consisting of macrophages containing numerous mitochondria, abundant rough endoplasmic reticulum, and secondary lysosomes filled with digested myelin debris and other electron-dense material. Within macrophages, myelin fragments undergoing active digestion, lyre-like bodies and paracrystalline inclusions were frequently noted. Astrocytes and their processes were prominent; glial filaments and many mitochondria were readily detected. Proliferation of inner mesaxons was observed. Cross-sectional profiles of innumerable myelinated fibres contained membranous organelles continuous with the inner lamellae of the oligodendroglial cells. The proliferations of inner mesaxons formed whorls and loops, and intrusion of the membranous tongue of the inner mesaxon into the axoplasm was occasionally observed; dystrophic neurites were relatively numerous. In mice infected with the Fujisaki strain of GSS, fibres had undergone demyelination with stripping of the myelin lamellae, while others showed vesicular myelin degeneration.
Animals↗
Strain-dependent antibody response induced by DNA immunization.
The antibody (Ab) response induced by DNA-based immunization was compared in various strains of inbred, H-2 congenic and outbred mice with different haplotypes of mouse major histocompatibility complex (H-2). Two different plasmid expression vectors encoding Aequorea victoria green fluorescent protein (GFP) or Escherichia coli, beta-galactosidase (beta-gal) were introduced into quadriceps muscle, and Ab production was examined using both enzyme-linked immunosorbent assay and immunoblot analysis. The beta-gal plasmid DNA immunization induced strong Ab production in all inbred, H-2 congenic and outbred strains at the early stages of immunization. By comparison with beta-gal peptide immunization, the degree of Ab response was H-2 haplotype-dependent. On the other hand, Ab production by GFP plasmid DNA immunization was observed in outbred strains, but not in some of the inbred and H-2 congenic strains. Also, outbred strains showed a high Ab response compared with other inbred and H-2 congenic strains by GFP peptide immunization. Reverse transcription-polymerase chain reaction analysis demonstrated the presence of GFP or beta-gal transcripts at the DNA inoculation site in all the strains studied, even in inbred and H-2 congenic strains which showed no Ab production by GFP plasmid DNA immunization. These results indicate that the difference in Ab response induced by DNA immunization as well as by peptide immunization depends upon the H-2 haplotypes of host strains.
Animals↗
Cloning of a rat gene encoding the histo-blood group B enzyme: rats have more than one Abo gene.
A genomic DNA fragment corresponding to exon 7 of the human ABO gene was amplified from rats of several inbred and outbred strains. Five different sequences were obtained, four of them corresponding to A-type sequences and one to a B-type sequence based on the amino acids equivalent to residues at positions 266 and 268 of the human enzymes. In rats from inbred strains, a single A-type sequence and the unique B-type sequence were found, whereas some animals of outbred strains presented two or three A-type sequences along with the B-type sequence. The complete coding sequence of the B-type gene was obtained; identification of the exon-intron boundaries, determined by comparison with rat genomic sequences from data banks, revealed that the rat B-type gene structure is identical with that of the mouse Abo gene. Compared with the human ABO gene and the rat A gene, it lacks exon 4. Like the rat A gene (symbol: Abo), the rat B gene (symbol: Abo2) is located on chromosome 3q11-q12. It could be shown by transfection experiments that the B-type cDNA encodes an active B transferase. A transcript of the B gene was found ubiquitously, whereas the B antigen was only detected in a restricted set of tissues. These data indicate that rats have at least two distinct Abo genes, one monomorphic gene encoding a B-specific enzyme and one or more genes in some cases encoding an A-specific enzyme.
ABO Blood-Group System↗
The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder.
The dopamine D4 receptor (D4R) is a candidate gene for attention deficit/hyperactivity disorder (ADHD) based on genetic studies reporting that particular polymorphisms are present at a higher frequency in affected children. However, the direct participation of the D4R in the onset or progression of ADHD has not been tested. Here, we generated a mouse model with high face value to screen candidate genes for the clinical disorder by neonatal disruption of central dopaminergic pathways with 6-hydroxydopamine (6-OHDA). The lesioned mice exhibited hyperactivity that waned after puberty, paradoxical hypolocomotor responses to amphetamine and methylphenidate, poor behavioral inhibition in approach/avoidance conflict tests and deficits in continuously performed motor coordination tasks. To determine whether the D4R plays a role in these behavioral phenotypes, we performed 6-OHDA lesions in neonatal mice lacking D4Rs (Drd4(-/-)). Although striatal dopamine contents and tyrosine hydroxylase-positive midbrain neurons were reduced to the same extent in both genotypes, Drd4(-/-) mice lesioned with 6-OHDA did not develop hyperactivity. Similarly, the D4R antagonist PNU-101387G prevented hyperactivity in wild-type 6-OHDA-lesioned mice. Furthermore, wild-type mice lesioned with 6-OHDA showed an absence of behavioral inhibition when tested in the open field or the elevated plus maze, while their Drd4(-/-) siblings exhibited normal avoidance for the unprotected areas of these mazes. Together, our results from a combination of genetic and pharmacological approaches demonstrate that D4R signaling is essential for the expression of juvenile hyperactivity and impaired behavioral inhibition, relevant features present in this ADHD-like mouse model.
Amphetamine↗
Protection against cutaneous leishmaniasis in outbred vervet monkeys using a recombinant histone H1 antigen.
Infection with Leishmania major parasites results in the development of cutaneous ulcerative lesions on the skin. We investigated the protective potential of a single, recombinant histone H1 antigen against cutaneous leishmaniasis in an outbred population of vervet monkeys, using Montanide adjuvant. Protection was assessed by challenging the animals with a mixture of vector sand fly salivary-gland lysate and a low dose of in vitro-derived parasites, thus more closely mimicking natural infection induced by L. major. The course of infection in immunized monkeys was compared with that of animals that had healed from a primary infection and were immune. The monkeys immunized with recombinant histone H1 showed a reduced development of lesion size, compared with controls. Our study therefore illustrates the potential use of histone H1 as a vaccine candidate against cutaneous leishmaniasis in humans.
Adjuvants, Immunologic↗