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J Buelke-Sam

Publications and source records attributed to J Buelke-Sam.

At least 19 recordsLinked to original sources
PubMed1987

Practical considerations in establishing reliable and sensitive neurobehavioral test methods.

The use of animal models in the safety assessment of compounds requires that the methods employed be established as reliable, sensitive and valid indicators of toxicity. Neurobehavioral toxicology is in a unique position due to recent efforts in this area prior to incorporation into routine screening systems. Aspects of study design and general implications of results are discussed from the Collaborative Behavioral Teratology Study, a large-scale effort specifically undertaken to evaluate the reliability and sensitivity of a standardized behavioral teratology test protocol. In control animals in any given measure used, comparable trial-, day- or age-related patterns were obtained in all 6 participating laboratories. In addition, prenatal treatment-related alterations observed were consistent within and across laboratories in both the amphetamine and methylmercury studies. For the majority of endpoints monitored, coefficients of detection calculated from vehicle control data estimated that a 5-25% change in behavior in treated groups could be detected statistically. Thus, with use of an adequate design and sample size within a standardized protocol, it is possible to identify the presence or absence of behavioral change with some confidence.

Animals↗
PubMed1986

Prenatal reserpine exposure in rats decreases caudate nucleus dopamine receptor binding in female offspring.

The effects of prenatal exposure to reserpine on [3H]spiroperidol binding in caudate nucleus at postnatal day (PND) 21 were investigated. Pregnant rats were dosed with 0, 0.375 or 0.750 mg/kg/day reserpine s.c. on days 12-15 of gestation. At PND 21, pups were killed and their brains were dissected and stored at -70 degrees C for analysis. Dopamine receptor binding was measured in membrane prepared from caudate nucleus of both sexes over a [3H]spiroperidol concentration range of 0.02 to 2.0 nM. Scatchard analysis revealed that the number of dopamine receptors (Bmax) in the membrane of female caudate nucleus was significantly decreased in a dose-dependent manner, while the dissociation constant (KD) was relatively unchanged. In male rats, neither Bmax nor KD was significantly reduced in either dose group. These results show that prenatal exposure to reserpine decreased the dopamine receptor number in caudate nucleus in a sex-dependent manner. This alteration may underly several sex-related behavioral changes that were previously found in offspring from identically treated dams.

Animals↗
PubMed1986

Early neurobehavioral and neurochemical alterations in rats prenatally exposed to imipramine.

Pregnant CD rats were treated subcutaneously with 0, 5 or 10 mg/kg/day of imipramine (IMI) on days 8-20 of gestation. Behavioral and neurochemical endpoints were measured at different postnatal days (PND). Three behavioral tests were conducted: negative geotaxis on PNDs 7-9; auditory startle habituation (ASH) on PNDs 14, 16 and 18; locomotor activity before and after intraperitoneal (i.p.) injection of saline or 0.5 mg/kg d-amphetamine on PND 21. Catecholamine levels, B-adrenergic and muscarinic cholinergic binding were measured on PND 1 and in PND 21 rats 3 hours after challenge. Maternal weight gained during the dosing period was decreased in a dose-related manner, but there were no dose-related differences in offspring body weights. On PND 7, low-dose males turned significantly sooner in negative geotaxic testing, and more high-dose males successfully turned (94%) than did controls (61%). A significant reduction in ASH amplitude was found only in males from the low-dose group on PND 18. IMI-exposed males tended to be more active prior to and following amphetamine challenge. On PND 1, male offspring from the low-dose group showed a 65% reduction in B-adrenergic receptor binding and a trend toward increased brain epinephrine (EPI) levels. On PND 21, no consistent dose-related receptor binding changes were observed. Cortical levels of EPI, however, tended to be higher in treated males and high-dose females challenged with d-amphetamine. These same rats also showed a marked elevation in locomotor activity following challenge with d-amphetamine. Thus, prenatal IMI exposure appeared to alter functional development of the central adrenergic systems in a complex manner, but one consistent with changes noted in both neurochemical and behavioral endpoints.

Analysis of Variance↗
PubMed1984

Sex and strain differences in the developmental activity profile of the rat tested over clean vs home cage bedding.

In the first of two experiments, CD rat litters were used to characterize activity patterns obtained in a size-adjustable, single photodetector chamber. Beginning on postnatal Day 10 or 12, pups were tested repeatedly over clean bedding (C) or over bedding removed from each pup's home cage (HC). In C rats of both sexes and in HC females, short-term activity levels peaked on Day 16. However, HC males displayed an earlier and even greater elevation in activity from Day 12 to 16. This overall pattern was found in rats tested either every second or fourth day. In the second experiment, Long-Evans pups were assigned to each testing condition (C vs HC) and activity measured beginning on Day 12. Peak levels were seen in all Long-Evans rats on Day 16 and only females showed significant alterations as a function of bedding condition. When overall activity levels of the two strains were compared, significant differences were found on Days 12, 24, 30, and 120 in males, and 12, 24, and 30 in females. Significant differences between strains in activity as a function of bedding condition were found in males on Days 12, 20, 24, and 120 and in females on Days 12, 30, and 60. These data confirm the generality of a developmental hyperactivity phase in isolated juvenile rats. However, different patterns of hyperactivity were found in male vs female rats across strains. CD males were more active in the presence of HC olfactory cues, while in Long-Evans rats, female activity was affected more by bedding condition.

Age Factors↗
PubMed1984

Postnatal toxicity following prenatal reserpine exposure in rats: effects of dose and dosing schedule.

Pregnant CD rats were treated subcutaneously with 0, 0.1, 0.33, or 1.0 mg reserpine/kg/day either on Days 12-15 or on Days 16-19 of gestation. Dams were allowed to deliver and litters (4 +/- 1 of each sex) were weighed weekly and held to 21 days of age. Basal ornithine decarboxylase (ODC) activity and neurochemical determinations were made on hearts and brains, respectively, from pups culled from litters on postnatal Day 1, and from two males and two females/litter at 21 days of age. Following both treatment schedules, the high dose of reserpine resulted in maternal weight loss during dosing, increased stillborn pups, reduced pup weight at birth, retarded postnatal growth, and decreased survival to 21 days of age. Basal cardiac ODC activity was reduced to 33% of control levels only on Postnatal Day 1 in both high-dose groups, while absolute heart weight decreased and relative heart weight increased in these pups. Whole-brain concentrations of two neurotransmitter metabolites, 3-4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA), were increased only at Postnatal Day 1 in the high dose group treated on Days 12-15 of gestation. No other changes were found in concentrations of these metabolites or in the transmitters dopamine and serotonin. The only effect found following administration of 0.33 mg/kg reserpine was a reduction in maternal weight gained during both dosing periods. No signs of toxicity were observed following low-dose exposure on either schedule. Most previously reported postnatal functional studies following reserpine exposure have used mid- to late-gestational treatment with 1.0 mg/kg, a dose shown here to result in marked overt maternal and fetal toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Blood flow during pregnancy in the rat: I. Flow patterns to maternal organs.

Normal blood flow patterns to several maternal organs were characterized in individual CD rats, nonpregnant (NP) or on day 6, 7, 8, 10, 11, 12, 13, 16, 18, or 20 of gestation using the radioactive microsphere technique. Weights and flow values were determined for several uterine tissue samples as well as maternal organs. No significant changes were found in blood flow to the stomach, spleen, and urinary bladder of these animals. There also were no remarkable changes as pregnancy progressed in blood flow to the lungs, suggesting that no marked arterial-venous shunting occurs in maternal placental tissues over gestation. Slight but consistent decreases in absolute (ml/min) and relative (ml/min/g tissue) blood flow to the brain were noted, and percent cardiac output (CO) was significantly decreased on all days of gestation except day 7. Complex changes were observed in blood flow to the kidneys, liver, adrenals, and heart. Absolute flow to the kidneys and liver reached maximum values on day 11, although percent CO delivered to both organs was consistently reduced throughout gestation. Absolute flow to the heart and adrenals peaked on day 13 and days 11-12, respectively. Absolute flow to the ovaries increased nearly 5-fold from the NP state (0.36 +/- 0.11) to day 20 of pregnancy (1.61 +/- 0.33). Interlitter differences in ovarian blood flow during midgestation were found to be a result of differences in litter size and distribution of embryo/fetuses between the two uterine horns. The fact that the majority of changes observed in maternal organ flow coincide with placental development, rapid augmentation of total uterine flow, and/or maternal hormonal changes suggests that these patterns may be important indicators of the dynamic physiology of pregnancy.

Animals↗
PubMed1982

Blood flow during pregnancy in the rat: II. Dynamics of and litter variability in uterine flow.

Normal blood flow patterns were characterized in individual CD rats, nonpregnant (NP) or on day 6, 7, 8, 10, 11, 12, 13, 16, 18, or 20 of gestation using the radioactive microsphere technique. Five animals were evaluated at each stage of pregnancy. Weights and flow values were determined for several maternal organs and uterine tissue samples. Embryo/fetal (E/F) sex was determined from day 11 on by measuring the prevalence of nuclei with sex chromatin in amnion smears. There was a marked increase in absolute flow to the uterus and all uterine contents during gestation (0.28 +/- 0.13 ml/min to the NP, diestrous uterus; 9.07 +/- 0.97 ml/min on day 20 of pregnancy). However, relative blood flow (ml/min/g tissue) decreased by day 20 to one-third NP values. Thus, though blood flow greatly increased, it did so at a rate lower than total tissue growth (including the uterus, placental tissues, and the E/F itself). There was a rapid redistribution of blood flow from the decidua parietalis (DEC) to the chorioallantoic placenta (CAP) on days 11-13, with nearly equal flow being delivered to the CAP and DEC of the "average" embryo on day 12 of gestation. By day 16 the DEC functionally had atrophied, and nearly 100% of the flow was delivered to the CAP. Male E/Fs tended to weigh more than female; however, these differences were statistically significant only on days 13, 18, and 20. E/F sex was not found to be strongly related to any of the variables evaluated in this study except E/F weight. Significant interlitter variability in E/F weight and blood flow consistently was observed at all gestational stages. Differences in litter size and E/F distribution within the two uterine horns did not account for the majority of this variability.

Animals↗
PubMed1978

Comparative stability of physiological parameters during sustained anesthesia in rats.

Rats were anesthetized with pentobarbital, pentobarbital and atropine, inactin [5-ethyl-5-(1'-methyl-propyl)-2-thiobarbiturate], ether and inactin, or urethane. Cardiovascular and arterial acid-base parameters were monitored over a 3-hour period of anesthesia. Heart rate, arterial pressures, and pH progressively decreased with duration of pentobarbital anesthesia. Changes observed in rats anesthetized with the thiobarbiturate, inactin, were similar although generally less severe. Most subjects treated with the barbiturates were markedly hypercapnic. Urethane anesthesia was characterized by a higher and more stable heart rate and greater pulse pressure. Arterial carbon dioxide and bicarbonate levels in the urethane group were substantially lower at all sampling times than the values obtained in the barbiturate groups.

Acid-Base Equilibrium↗
PubMedDate not supplied

Postnatal function following prenatal reserpine exposure in rats: neurobehavioral toxicity.

Behavioral and neurochemical analyses were conducted on preweanling CD rats prenatally exposed to either 0, 0.375 or 0.750 mg/kg/day reserpine SC on gestation days 12-15. Offspring body weights were taken on test days, and pups were tested for negative geotaxis responding on postnatal day 8, developmental activity on days 12, 16 and 20, and auditory startle habituation on day 19 or 20. In addition, brains were removed from culled pups on day 1, 1 male and 1 female/litter on day 8, and animals tested for activity on day 21. Neurochemical assays were performed on whole brains from 1- and 8-day-old pups, and on caudate nucleus, frontal cortex and hippocampus of day 21 rats. Treatment resulted in dose-related decreases in maternal weight gain over gestation and mean pup weight at birth. Changes in the normal developmental activity pattern were both sex and dose dependent in treated rats. In auditory startle habituation experiments, rats exhibited a dose-related decrease in response amplitude and rate of habituation. In the day 21 females, caudate nucleus dopamine (DA) and serotonin (5-HT) concentrations and DA-receptor binding were decreased in a dose-dependent manner. Males showed less dramatic, but similar trends in caudate changes. However, hippocampal 5-HT and 5-HT receptor binding were significantly reduced only in females. Thus, sex-related behavioral alterations were accompanied by sex-related neurochemical changes, and females generally were more affected than males by prenatal reserpine treatment. The significant decrease in activity and auditory startle amplitude in the females is consistent with the suggested down regulation of the DA system in regional brain areas.

Animals↗
PubMedDate not supplied

Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group II report: testing methods in developmental neurotoxicity for use in human risk assessment.

The Work Group addressed the design and content of a basic screening battery for detecting or flagging developmental neurotoxicity. It was agreed that a basic screening battery should be incorporated routinely into any developmental or reproductive toxicity study conducted for risk assessment purposes, and that a "triggered" stand-alone developmental neurotoxicity study, as exemplified by the current EPA proposal, should include greater in-depth evaluation of CNS function and pathology. Time constraints did not permit the group to address the design or content of such a stand-alone study. It was acknowledged unanimously that a basic screening battery may provide more information than simply the detection of neurotoxicity; however, it should not be expected to provide detailed dose-response information nor to identify the precise mechanism of agent action. The Work Group also agreed that a basic screening battery should include evaluation of multiple CNS functions, that observed alterations may be indicative of primary or secondary effects on the nervous system, that the test methods selected may differ based on what is known about the agent, and that the protocol for study conduct can be as important as the methods employed. In light of these assumptions, the Work Group recommended schedules for monitoring offspring development using measures of: 1) physical landmarks, 2) brain weights, 3) neuropathology, 4) functional observations, 5) motor activity, 6) reactivity, and 7) learning and memory. The species tested, sample sizes, treatment parameters, etc., would be determined by the type of developmental or reproductive toxicity study into which the basic screening battery was incorporated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Developmental toxicity of the dopamine agonist pergolide mesylate in CD-1 mice. I: Gestational exposure.

Pergolide was given by oral gavage to mated CD-1 female mice at doses of 0, 1, 20, or 60 mg/kg/day on gestation days (GD) 6-15. Animals assigned to the teratology segment were killed on GD 18 for evaluation of maternal organ weights, and fetal viability, weights and morphology. Animals assigned to the postnatal segment were allowed to deliver and physical development and behavioral performance of the progeny were monitored until weaning. Maternal organ weights were collected at termination after weaning. One F1 offspring per sex per litter was maintained for postweaning physical, behavioral and reproductive assessments and for terminal examinations and organ weight evaluations. No adverse effects of pergolide treatment were found in the 1 mg/kg/day group. Dose-related hyperactivity, chewing and squinting that were consistent with dopaminergic stimulation occurred following dosing in the 20 and 60 mg/kg/day groups; F0 body weights and food consumption were reduced during the initial phase of treatment in the 60 mg/kg/day group. Gravid uterine weights and fetal weights were decreased in the 60 mg/kg/day group of the teratology segment, but there was no indication of teratogenicity in any group. Mammary inflammation, attributed to increased progeny suckling, occurred during the second week postpartum in a few postnatal segment females of the 20 and 60 mg/kg/day groups. Mean negative geotaxis performance was delayed slightly, but mean progeny survival and body weights were not affected. Although after weaning the F1 offspring from the treatment-derived groups tended to weigh more than controls and to perform more effectively in the active avoidance task, these findings were attributed to unusually low values obtained in the control group. Startle amplitudes were increased significantly in the males from the 60 mg/kg/day treatment-derived group. These dose-related maternal and developmental findings were all consistent with the mixed D1/D2 agonist properties of pergolide mesylate, and suggest that only very high doses may result in persistent effects on the developing central dopaminergic systems.

Aging↗
PubMedDate not supplied

Developmental toxicity of the dopamine agonist pergolide mesylate in CD-1 mice. II: Perinatal and postnatal exposure.

Pergolide mesylate is a dopamine agonist and, therefore, reduces prolactin secretion. In Experiment I, pregnant mice were given oral doses of 0, 0.1, 0.3, 1.0 or 3.0 mg/kg/day pergolide on GD 15 through PD 10 or 20 to identify a tolerated dose which would not markedly reduce offspring survival during late gestational and lactational exposure. Offspring survival was not affected at any dose, but dose-related decreases in progeny body weights occurred at weaning. On PD 10, suckling-induced increases in maternal serum prolactin concentrations did not occur in dams treated with 3.0 mg/kg/day. In Experiment II, pregnant mice were given oral doses of 0, 0.002, 0.1 or 3.0 mg/kg/day pergolide on GD 15 through PD 20. Dams were allowed to deliver and maintain their offspring throughout a 21-day lactation period. Growth and behavioral performance of one F1 male and one F1 female per litter were monitored, followed by a reproduction trial and terminal organ weight measurements. There were no treatment-related effects on maternal body weights, food consumption, or terminal organ weights and pathology. Three dams showed overt signs of mammary inflammation and lactational insufficiency and mean progeny survival was decreased slightly in the 3.0 mg/kg/day group. There were no adverse effects on growth, development or reproductive performance in the F1 treatment-derived generation. Neonatal negative geotaxis, 1-h activity levels at 30 and 60 days of age, auditory startle habituation at 55 days of age, and two-way active avoidance performance at 65 days of age were not affected significantly by treatment. Thus doses of pergolide that did not inhibit lactation completely in the F0 dams were found to have no enduring effects on offspring development.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

The use of repeated measures analyses in developmental toxicology studies.

In many toxicology studies, it is common to take the same measurements on an individual animal at several time points (e.g., body weight across days or weeks, activity levels either within a single test session or across days). Such repeated measures for both maternal and offspring endpoints routinely are incorporated into developmental toxicology studies to allow characterization of the profile of treatment-related effects over time. To permit a valid statistical analysis, repeated measures studies are characterized by: random assignment of treatment to experimental units, measurement of the variable(s) of interest at the same time points for all animals, and avoidance of systematic overlaying of treatment and potential response gradients. Assumptions for and advantages of the use of a repeated measures analysis of variance versus single-factor analyses at each time point are illustrated in two data sets from a rat perinatal and postnatal study. The variance-covariance structure of repeated measures designs dictates that adjustments are necessary to provide protection against inflated Type 1 error rates. Communication between statisticians and toxicologists which allow the implementation of such analyses can improve the interpretation of data resulting from repeated measures study designs.

Analysis of Variance↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: background and overview.

Organization of the Collaborative Behavioral Teratology Study began in 1978 because of concern about potential postnatal dysfunction following developmental chemical exposure. The study design was focused primarily on the evaluation of reliability of behavioral testing methods, the sensitivity of these methods to alterations produced by prenatal chemical exposure, and the effects of litter, sex of the animals and prior testing experience on behavioral responses. The test methods and chemicals used were selected from the literature available at that time using certain specific criteria. NCTR served as the pilot testing laboratory, and five additional laboratories participated in the study, using a standardized protocol, testing equipment and procedures. The results of the study are presented in other papers in this issue, and give ample evidence for consistency of the behavioral measures used within and between studies, and within and between laboratories. The issues of sensitivity, sex, litter and prior testing experience were addressed within the framework of this study design, but further systematic evaluation of chemicals and methods is encouraged, as exemplified by the invited papers in this issue.

Behavior↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: preliminary research.

Prior to the beginning of the Collaborative Behavioral Teratology Study (CBTS), extensive preliminary experiments were conducted. Several experiments were conducted to permit the selection and verification of dosage levels of d-amphetamine sulfate and methylmercuric chloride to be used in the CBTS. These studies included evaluations of any teratogenic effects produced by selected concentrations of the chemicals, the potential pathology produced in the dams and offspring, and the postnatal behavioral consequences of the prenatal exposures. This preliminary research allowed the determination of the most appropriate experimental design for the CBTS, verified the practicality of the schedule of work, assured that all necessary procedural details were specified, and provided a database for the determination of the most appropriate statistical techniques for the analyses of the data. This paper presents the details and results of the preliminary research performed prior to beginning the CBTS.

Animals↗
PubMedDate not supplied

Collaborative Behavioral Teratology Study: protocol design and testing procedures.

This paper presents background information on the methods used in the Collaborative Behavioral Teratology Study (CBTS), the rationale behind the experimental design, and the design and specific procedures used in the CBTS. Each of the following methods is discussed: negative geotaxis, olfactory discrimination, auditory startle habituation, one-hour activity in the figure-8 maze, visual discrimination learning, 23-hour activity in the figure-8 maze, and amphetamine-stimulated activity. The CBTS was designed to determine the intra- and interlaboratory reliability of these test methods and the detection sensitivity of each method, as well as to determine the importance of several major variables (early test experience, gender, litter). The important design features which permitted these evaluations are discussed. Each laboratory conducted two independent experiments: one using d-amphetamine sulfate as the test agent and one using methylmercuric chloride. Other than the use of different agents and dosing regimens in the two studies, all other characteristics of experimental design were identical. Each study was conducted in four replicates with 4 litters/each of 4 treatment groups/replicate. The replicate design was an important feature which permitted reliability of the tests to be addressed under conditions in which several other sources of variation in responding could be identified and accounted for in the model. Other methods by which optimal testing conditions were implemented in the participating laboratories included the "blind" testing of all subjects in specific orders which were counterbalanced for treatment group, time of day, and the apparatus in which the animals were placed.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗