Animal models in behavioral toxicology and teratology.
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Animals↗
Biomedical subjects
J Elsner
Publications and source records attributed to J Elsner.
Single cell analysis in toxicity testing: the mitogenic activity of thioacetamide in cultured rat hepatocytes analyzed by DNA/protein flow cytometry.
Rat hepatocytes were cultured at 4% O2 and 13% O2 and exposed to the nongenotoxic rodent carcinogen thioacetamide (TA) from 24 to 72 h after isolation at exposure levels between 0.01 and 0.33 mM. Hepatocytes and isolated nuclei were analyzed by DNA-protein flow cytometry. An aggregate correction procedure was applied and the proportion of S-phase, diploid, tetraploid or octoploid hepatocytes as well as binucleated cells, were measured or calculated. The proportion of S-phase cells within the diploid hepatocytes increased with increasing concentration of TA up to 3.9-fold, whereas the corresponding increase in S-phase mononucleated tetraploid cells was only 1.8-fold. S-phase binucleate tetraploid cells showed no increase. In the tetraploid hepatocytes, the mitogenic stimuli was detectable only in cultures maintained at 4% O2. The relative contribution of binuclear cells was increased 1.5-fold in the octoploid cells. It is concluded that the mitogenic activity of TA initiates DNA synthesis in diploid hepatocytes in the G1 and in the following G2 cell-cycle phase, omitting karyogenesis. The cellular protein content is not affected which indicates that the mitogenic activity of the chemical is not necessarily associated with an increase in cellular protein content. The results obtained correspond well with data of in vivo studies. The method applied therefore allows the mitogenic activity of nongenotoxic carcinogens to be detected in vitro within 48 h and their mode of action to be elucidated.
Animals↗
Tactile-kinesthetic system of rats as an animal model for minimal brain dysfunction.
A previous study showed that rats exposed to methylmercury during development exhibit effects similar to those described for children with minimal brain dysfunction (MBD), namely, hyperactivity, altered locomotion structure, and unaltered learning ability, but reduced and more variable attention spans induced by increasing difficulties within an operant learning paradigm. Psychopathological studies suggest that behavioral disturbances of the MBD type may originate directly or indirectly from deficiencies in the tactile-kinesthetic system. This sensory modality is the main mechanism by which an individual organism assimilates reality. Deficiencies in the tactile-kinesthetic system impair the action of the equilibration processes (in Piaget's sense) which ensure that the stages of psychological development occur in an orderly sequence. The lack of this control over development may result in the behavioral characteristics of MBD. Problems with the tactile-kinesthetic system may also be the reason for the deficiencies of fine motor control in MBD children. In an attempt to extrapolate this interpretation of human psychopathological mechanisms to experimental animals, an operant paradigm was developed for the assessment of the tactile-kinesthetic system of rats, the schedule of "differential reinforcement of force range" (DRF). Rats were trained to press in discrete trials a force sensitive lever during at least 1 s between two force thresholds of 60 and 80 g without any feedback other than the rats' own tactile-kinesthetic perception. Offspring of rat dams exposed to 1.5 and 5 mg/l methylmercury-chloride in their drinking water from 2 weeks before pairing until weaning, exhibited a clearcut performance deficit (approximately 25% correct responses compared to approximately 50% of the controls).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Granulocyte and granulocyte-macrophage colony-stimulating factors for treatment of neutropenia in glycogen storage disease type Ib.
Two children with glycogen storage disease type Ib associated with numerous recurrent bacterial infections as a result of neutropenia and neutrophil dysfunction were treated with recombinant human granulocyte colony-stimulating factor (G-CSF). One of the two patients was previously treated with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF); therapy had to be discontinued because of severe local side effects. Both colony-stimulating factors at dosages of 3 and 8 micrograms/kg/per day, respectively, increased the average neutrophil counts from less than 300 cells/microliters to more than 1200 cells/microliters. Two subpopulations of neutrophils could be identified by their capacity to produce H2O2: one subpopulation generated H2O2 normally and a second was defective in H2O2 production. The doses of G-CSF effectively enhanced and maintained that subpopulation of neutrophils which produced normal amounts of H2O2. Moreover, these colony-stimulating factor-induced neutrophils demonstrated effective phagocytosis of zymosan particles and killing of staphylococci. Chemotaxis was decreased and could not be normalized by treatment with G-CSF. We conclude that maintenance treatment with G-CSF improved the quality of life in both patients: The number and severity of bacterial infections decreased markedly during treatment. Long-term treatment with G-CSF (12 and 10 months, respectively) was well tolerated, and no adverse clinical events were observed.
Adolescent↗
In vitro functions of neutrophils induced by treatment with rhG-CSF in severe congenital neutropenia.
Neutrophils (and monocytes) from 5 patients suffering from severe congenital neutropenia (SCN) were investigated in vitro after induction of this cell type by treatment with recombinant human granulocyte colony-stimulating factor (rh G-CSF) in vivo. Some abnormal morphological features were seen, such as anomalies of nuclei of phagocytes. No limitations were found 1) in the ability of neutrophils and monocytes to produce reactive oxygen intermediates (ROI) following stimulation with phorbol-myristate-acetate (PMA), 2) in the ability of neutrophils to phagocytose particles of zymosan A and to produce ROI simultaneously and 3) in the ability to kill bacteria of the species staphylococcus aureus. However the specific migration of neutrophils in a gradient of FMLP under soft agar was decreased to approximately 50% in all patients tested as compared to healthy controls. In addition, spontaneous motility was decreased in one patient. Nevertheless, the good clinical improvements of patients suffering from SCN after treatment with rh G-CSF appeared to be due to induction of neutrophils displaying overall good functional activities with respect to natural defense.
Blood Bactericidal Activity↗
Treatment with methylazoxymethanol at different gestational days: two-way shuttle box avoidance and residential maze activity in rat offspring.
Pregnant rats were injected with a single dose of methylazoxymethanol (MAM, 25 mg/kg) on gestational days 14, 15, 16, 17, 18 or 19 which resulted in various degrees of microencephaly. Offspring were tested on a two-way shuttle box avoidance and residential maze activity at 60-90 days of age. Rats treated on gestational day 19 (GD19) were severely impaired in the acquisition of the two-way shuttle box task whereas the other groups did not show any significant difference from controls. Spontaneous activity measured for 23 hr in the residential maze was altered as total, time-course and pattern depending on the time of MAM administration: treatment on GD14 prolonged exploratory behavior, treatment on GD15 and GD16 increased nocturnal activity, treatment on GD16 and GD17 induced changes in locomotion patterns and treatment on GD18 and GD19 decreased total activity. These findings indicate that treatment with MAM results in selective deficits in the acquisition of a shuttle box avoidance and alterations of locomotion patterns in the offspring which are dependent on the time of administration.
Alkylating Agents↗
Effects of phenylethylamine on rat locomotor behavior and avoidance learning.
1. The effects of beta-phenylethylamine (PEA) alone and in association with caroxazone, a potent inhibitor of monoamine oxidase B (MAO B), on the activity and long-term memory in the wheel-shaped activity monitor and on fixed-interval two-way avoidance acquisition were studied in rats. In a separate study, we determined the effects of PEA and of d-amphetamine on the variable-interval two-way avoidance acquisition. 2. The action of PEA was markedly different from that of amphetamine in several aspects. The stimulating effects of PEA in the wheel-shaped activity monitor were of a more subtle nature than those of amphetamine and in the variable-interval two-way avoidance acquisition PEA had no effect, while amphetamine improved performance. 3. PEA did not induce an increase in path-choice stereotypy, but caroxazone did. The absence of any caroxazone-session interaction effects on the path iteration frequency suggested that there were no long-term memory effects. 4. In the fixed-interval two-way avoidance acquisition experiments, PEA increased the avoidance responses of rats while caroxazone had no effect. The association of the two drugs did not potentiate either.
Animals↗
Interaction between ethanol and caffeine in operant behavior of rats.
The interaction between ethanol and caffeine on operant behavior was studied in 24 water-deprived male rats trained in a discrete trial spatial alternation schedule with water as reinforcer. One single drug dose-response experiment or one dose combination of ethanol and caffeine (including the associated control treatments) was run on 4 successive days in 1 week. The four treatments of 1 week were administered to each animal in a distinct order according to the 24 possible permutations. In the single drug weeks, ethanol (0.25, 0.5, 0.75 and 1.0 g/kg IP) or caffeine (5, 10, 20, and 40 mg/kg PO) were administered 15 min before the session. In four interaction experiments all combinations of two doses of ethanol (0.5 and 1.0 g/kg IP) and two doses of caffeine (25 and 50 mg/kg PO) were employed. Ethanol and caffeine alone showed both dose-dependently decreased choice accuracy and increased response latency and passiveness. In combination, caffeine normalized the ethanol-induced alterations in ITI response rate and pause length but potentiated the effects on choice accuracy, latency and number of pauses. The results are interpreted in terms of effects of these drugs on attentional and arousal processes, and the test procedure is proposed as a screening tool for the preclinical assessment of ethanol-drug interactions.
Animals↗
Neurobehavioral screening in rats: validation study.
The usefulness of a neurobehavioral check-list for the detection and characterization of neurotoxic effects of chemical compounds was evaluated in rats. The animals were given single doses of the test compounds, and higher or lower doses of the substances were administered in subsequent weeks, depending on the outcome of the experiments. The testing procedure proved to be useful for detecting the neurobehavioral hazards of psychotherapeutics and other drugs with known neurobehavioral side-effects. However, the investigational technique was less satisfactory for evaluating alcohols and various neurotoxic agents. With these compounds, even repeated dosing did not improve the predictability of the testing scheme. Swimming performance was also investigated and was found to be impaired only in rats treated with neuroleptic drugs. Based on this validation study, the advantages and pitfalls of the neurobehavioral check-list approach are discussed.
Alcohols↗
Behavioral effects of cyclazocine on rats assessed in the open field and residential maze.
Changes in behavior of rats caused by different doses of cyclazocine (0.1, 0.4, 0.75, 1.5, and 3.0 mg/kg) were detected by two different methods: the open field and the residential maze. In the residential maze the locomotion was recorded automatically, whereas in the open field the measurements were made by direct observation. In the maze low doses of cyclazocine (less than 1.5 mg/kg) caused a marked change in the time course of locomotion and local activity at the beginning of the 23-h sessions. The duration of this effect was dose-dependent, between 2 and 4 h. The highest dose (3 mg/kg) induced a strong stimulation of locomotor activity which lasted about 1 h, and stereotyped patterns, i.e., long periods of unidirectional runs through circular alleys. In the open field rearing and grooming behavior proved to be the most sensitive parameters. The frequency of both was reduced at a dose of 0.4 mg/kg. Locomotion showed the highest values at 1.5 mg/kg and decreased with the highest dose (3 mg/kg) to control levels. The study demonstrated that the principal changes induced by cyclazocine were of a qualitative nature, characterized by monotonous locomotor activity. The computerized residential maze procedure proved to be well suited to detect and quantify this behavioral change.
Animals↗
Toxicological screening.
Well-defined dose- and time-related toxic effects of chemicals can often be detected using simple tests with small numbers of animals. The strategies for the establishment of toxicological screening tests are discussed. The most important steps are the definition of the targets, the selection of the methods, and the setting of the test criteria. Screening tests must then be validated with standard reference chemicals, and the test criteria must be adjusted so that the standards can be detected regularly. Maximal flexibility is allowed in the design of the tests. For evaluation, the results obtained in treated animals can be compared with those of controls, using conventional concepts of biostatistics. It is also possible to base the evaluation on preset test criteria. Toxicological screening tests do not replace conventional safety studies, but they help in selecting the most promising candidates in a series of related chemicals and in establishing priorities for further testing. As an example, a screening for the hemolytic effects of chemicals is presented.
Drug Evaluation, Preclinical↗
Quantitative analysis of rat behavior patterns in a residential maze.
A method for monitoring spontaneous locomotor patterns of rats during one day is described. The animals' locomotion is registered in a residential maze by 18 optical gates connected to a computer. Status changes of each optical gate are stored on a disk file and can be retrieved for complete session reconstruction and data analysis. The general features of a rat's behavior in the maze are discussed. Quantitative analyses and statistical comparisons between two sessions spaced two weeks apart and between a group of 4 control animals and 4 rats treated in utero with methylmercury chloride are performed. Following parameters are analysed as functions of time and maze location: locomotor and local activity, occupational duration and time per visit in the maze compartments. Angular dependences of path decisions and regional preferences of crossing at the alley bifurcations are observed. No changes of the measured parameters can be observed between the first and second sessions. Methylmercury treatment results in a consistently lower local activity during the night period and in differences of path preferences.
Animals↗
Toxicological evaluation of imipramine in combination with adriamycin and strophanthin.
Chronic oral administration of imipramine to rats caused characteristic changes of the electrocardiogram (ECG), i.e. prolongation of the PR interval, widening of the QRS complex, and increase in T-wave voltage. The cardiotoxic anthracycline antibiotic adriamycin induced dose-dependent widening of the QRS complex. This effect on intraventricular conduction was not enhanced in rats receiving both drugs. The high adriamycin dose (5 x 4 mg/kg) abolished imipramine-induced prolongation of the PR interval and T-wave elevation. This was not seen with the low adriamycin dose (20 x 1 mg/kg). Imipramine prolonged survival time of rats treated with toxic doses of adriamycin, but enhanced growth retardation in animals receiving the low adriamycin dose. Chronic treatment with increasing doses of strophanthin induced significant flattening of the T wave in rats with and without imipramine therapy, but did not influence the changes of the ECG or body weight gain caused by imipramine. It is concluded that the combined use of imipramine and adriamycin or strophanthin did not lead to a serious enhancement of the toxicity of the tricyclic antidepressant.
Animals↗
Reminiscences of early Denver.
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History, Modern 1601-↗
[Use of cardiotachogram for the evaluation of circulatory regulation].
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Blood Circulation↗
[On the amount and significance of the effective glucose level in tumors. A contribution to the theory of cancer].
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Adenocarcinoma↗
[On qualities and installation of the electrocardiotachograph].
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Adult↗
Response force titration for the assessment of the neuromuscular toxicity of 2,5-hexanedione in rats.
A silent, non-moving glass lever combined with strain gauges and mounted in an operant chamber measured the vertical isometric force exerted by the forepaw of rats. Every weekday the rats were subjected to a force titration schedule consisting of a sequence of discrete trials signalled by a lever light. The required force, above which a water reinforcement is delivered, was regulated by a generalized bisection algorithm. A stable force level which the rat was able to attain at 50% of the trials was quickly reached in each session by this algorithm. This technique was used to measure the neuromuscular performance decrement due to repeated 2,5-hexanedione treatment (250 and 500 mg/kg/day per os). The results were compared with fore- and hindlimb grip strength measurements on the same animals. This experiment showed that the force titration technique is able to distinguish between motivational and true force decrements, a distinction which cannot be made by the grip strength technique.
Analysis of Variance↗