bluuebunny/crossref_metadata_2025_split huggingface dataset:
Status of safety pharmacology in the pharmaceutical industry—1995
Authors: Sullivan Andrew T. , Kinter Lewis B. 
Published: January 2005

AbstractSafety pharmacology contributes to the pharmacological characterization, risk assessment, and registration of new drugs; however, safety pharmacology strategies and study designs for new drugs vary widely across the pharmaceutical industry. We surveyed 26 pharmaceutical companies for how and why they conduct safety pharmacology studies. All conduct/contract safety pharmacology studies; 19 have safety pharmacology units, seven do not; ten locate responsibility for safety pharmacology in development, 16 in discovery (or research). Total staff range from two to 16 full‐time equivalents (fte)/unit. Most companies conduct evaluations of cardiovascular and CNS functions, less evaluate respiratory, gastrointestinal and renal functions; a few conduct a ligand‐binding/activity panel as part of their pharmacological profiling. Resources to complete a company's standard safety pharmacology program are ∼1–4 fte/compound. One‐third of companies use a maximum tolerated dose (MTD) for safety pharmacology studies, two‐thirds use multiples of pharmacological or therapeutic doses. Approximately half conduct safety pharmacology studies to Good Laboratory Practices (GLPs) and use the 1992 Japanese guidelines only as a guide or outline. Company clinicians are most often cited as the “primary customer” for whom Safety Pharmacology studies are done, followed by research and development scientists, and then regulatory authorities. The results suggest that most companies conduct safety pharmacology for its contribution to risk assessment and critical care management. © 1995 Wiley‐Liss, Inc.
Cellular distribution of the mRNA for the α7 subunit of the nicotinic acetylcholine receptor in the human cerebral cortex
Authors: Wevers A. , Sullivan J. P. , Giordano T. , Birtsch Ch. , Monteggia L. M. , Nowacki S. , Arneric S. , Schröder H. 
Published: January 2005

AbstractCentral nicotinic acetylcholine receptors (nAChRs) are ligand‐gated cationic channels characterized by a wide pharmacological and molecular diversity depending on the subunits involved. Recently a new type of a nicotinic acetylcholine receptor channel, highly permeable to calcium, consisting of α7 subunits which bear a binding site for the snake venom α‐bungarotoxin has been described. α‐bungarotoxin binding sites have previously been localized in the human and rat brain. Immunohistochemistry has revealed the presence of α7 subunits in the rodent CNS. Presently we have applied digoxigenin‐labeled RNA probes to localize α7 mRNA in human brain using autopsy samples of prefrontal (Area 10) and motor cortex (Area 4). α7 transcripts are expressed in numerous neurons throughout both cortical regions. Mainly pyramidal‐like neurons of layers II/III, V, and VI were labeled. In contrast to our previous studies on the localization of α3 and α4 transcripts, only a few giant pyramidal neurons in A4 but a rather high number of layer I neurons in A4 and A10 expressed α7 mRNA. The study shows that nicotinic receptor subunit mRNAs are distributed in a subunit‐ and area‐specific manner in the human cerebral cortex. These findings will be of importance as to the selective, ligand‐mediated stimulation of nicotinic receptor subtypes as a possible tool to improve cholinergic transmission in neurodegenerative disorders like Alzheimer's disease. © 1995 Wiley‐Liss, Inc.
Evaluation of the dependence liability of quinolizinones acting as partial agonists at the benzodiazepine receptor
Authors: Martin James R. , Moreau Jean‐Luc , Jenck François 
Published: January 2005

AbstractThe quinolizinones Ro 19‐5663, Ro 19‐5686 and Ro 41‐3696 bind with high affinity to the benzodiazepine receptor (BZR) in vitro in the rat brain. These compounds exhibit anxiolytic‐like effects in an operant punishment task in mice and rats and anticonvulsant effects by fully protecting against pentylenetetrazol‐induced tonic seizures in mice and rats and fully protecting against audiogenic seizures in genetically susceptible mice. However, they produced at most only minimal motor impairment in the rotarod task in rodents. These compounds attenuated flunitrazepaminduced sleep in squirrel monkeys, thus antagonizing the effects of a BZR full agonist. In a precipitated withdrawal paradigm, chronic oral treatment in seizure‐prone young DBA/2J mice or adult squirrel monkeys was followed by iv challenge with the BZR antagonist sarmazenil. Following the completion of a chronic treatment regiment with high doses of these quinolizinones, no signs of precipitated withdrawal were observed in mice and only weak signs of sarmazenil‐induced withdrawal were observed in monkeys. In contrast, sarmazenil challenge after chronic treatment with the BZR full agonists triazolam and alprazolam elicited marked withdrawal reactions in mice and monkeys, respectively. In sum, these quinolizinones are BZR partial agonists which offer potential anxiolytic and anticonvulsant efficacy concomitant to reduced adverse effects, including a clear reduction of dependence liability, in comparison to BZR full agonists. © 1995 Wiley‐Liss, Inc.
Development of membrane potentials of cortical cell elements in guinea pig fetus
Authors: Sedláček Jndřich 
Published: January 2005

AbstractThe mean membrane potentials of cellular elements were measured during the passage of a glass microelectrode through cortical tissue in fetuses and newborn guinea pigs. The average value of membrane potential increases in fetuses after the 47th day of gestation from 7.6 mV to 28.1 mV in newborn guinea pigs. The developmental changes in histograms of individual values correspond to the increase in mean value. The membrane potentials are sensitive to brain hypoxia following cord clamping only after the 62nd day of gestation. In term fetuses, cord clamping is followed by regular lung ventilation and by the slow gradual increase of mean value in membrane potentials. The development of the mean membrane potential of cortical elements correlates well with the development of the cortical steady potential.
Influence of age and brief auditory conditioning upon experimental seizures in mice
Authors: Iturrian W. B. , Fink G. B. 
Published: January 2005

AbstractAudio‐sensitivity can be induced in strains of mice considered audio‐resistant by exposure to a brief auditory stimulation (60 sec at 95 db) at a critical age. Mice that had been audio‐conditioned were subjected to a battery of seizure‐evoking procedures and the responses interpreted in terms of neurophysiological mechanism. The effect of maturation on the development of sound induced, chemoshock and electroshock convulsion threshold and pattern was also studied. The pattern of maximal seizures induced by electroshock, pentylenetetrazol, and sound are remarkedly similar at a given age. The threshold for low frequency electroshock and for minimal pentylenetetrazol decreased with increased age and weight. There was no significant difference in maximal electroshock seizure threshold with aging, but duration of the seizure pattern markedly changed with increased age. Audio‐conditioning produced profound changes in the ontogeny of low frequency and chemoshock threshold, but maximal seizure threshold and pattern were unaffected. The audio‐sensitized CF# 1 mice differ in several ways from littermate. The oscillator mechanism of the audio‐sensitive mice is more easily discharged by electric and chemical stimulation, and there is an alteration in the neuro‐ontogenic pattern, and a decreased growth rate.
Effects of age and stimulus conditions on the emotional response of rhesus monkeys: Diferential responses to frustration and to fear stimuli
Authors: Bernstein Stephen , Mason William A. 
Published: January 2005

AbstractLaboratory‐raised rhesus monkeys ranging in age from 3 to 25 months were tested for reactions to toys representing animals (“fear stimuli”) and to food frustration. The results indicate that these test conditions are associated with different response profiles and that the contrast between responses to fear and to frustration increases with age. Frustration in older animals is associated with regression to a less mature level of functioning.
Offspring survival, development, and operant performance following maternal ethanol consumption
Authors: Martin Joan C. , Martin Donald C. , Sigman Gary , Radow Barbara 
Published: January 2005

AbstractGravid Sprague‐Dawley‐derived rats received 35–40% of their total calories in alcohol during pregnancy or pregnancy and the 23‐day nursing period. Ethanol was administered both as the sole fluid source in a .1% saccharin solution and by twice daily subcutaneous injections. Two gravid control groups were matched for caloric and fluid intake to the experimental groups and received injections of the saline vehicle. The offspring were monitored from birth to adulthood on a variety of vital, developmental, and operant measures. Littermates of the behavioral offspring were sacrificed and necropsied at 1 and 12 months of age and the major organs examined for pathology.Differences between alcohol and control groups were found for maternal weight gain, length of gestation, number of neonatal deaths, growth retardation of offspring to postnatal Day 72, date of eye opening, distance traversed on Day 15, contingent performance in the 1st week on continuous reinforcement, fixed ratio, and timing appetitive schedules, and on number of shock initiations and ability to discriminate contingencies on punishment schedules. No gross abnormalities were observed in the major organs at necropsy.
Polygraphic studies of kitten development: Sleep state patterns
Authors: McGinty D. J. , Stevenson M. , Hoppenbrouwers T. , Harper R. M. , Sterman M. B. , Hodgman J. 
Published: January 2005

AbstractThe sequence of developmental changes in sleep pattern organization was derived from 12‐hr recordings in 10‐, 20‐ and 40‐day‐old kittens. Each characteristic of sleep patterning exhibited a distinct maturational sequence. Earlier changes (10–20 days) included quiet sleep (QS) increments and somatic activity decrements; later changes (20–40 days) included emergence of EEG slow waves and spindles, decrements in active sleep (AS), and diminution of QS respiratory variability. Changes in the lengths of state epochs and the types of state transitions spanned the period studied. We suggest that the differential development of the characteristics of sleep patterns reflects differential maturation of distinct nervous system elements.
The role of motor learning and cage size in the early enrichment effect in mice
Authors: Henderson Norman D. 
Published: January 2005

AbstractThree experiments with C57BL/10J mice examined the possible roles of cage size and simple motor practice as factors responsible for producing improved performance of animals reared in enriched environments. Neither factor was found sufficient to improve subsequent performance in a food‐seeking task. Mice reared in flat environments containing a variety of objects, but designed to prevent any climbing practice, out‐performed nonenriched animals on a task requiring extensive climbing activity.
Nocturnal sleep in isolation‐reared monkeys: Evidence for environmental independence
Authors: Reite Martin , Short Robert 
Published: January 2005

AbstractThirteen all‐night sleep recordings were obtained from 3 infant pigtailed (Macaca nemestrina) monkeys raised on a cloth surrogate mother under conditions of social isolation. Totally implantable biotelemetry systems were used to record the sleep physiology from the unrestrained animals. Sleep stages and night‐to‐night variability were virtually identical to values previously found in 8 mother‐reared group‐living infants. Sustained alterations in the early rearing environment, even though considerably modifying the organism's development, did not appear to result in differences in sleep organization.
Differential maternal retrieval of jaundiced versus non‐jaundiced gunn rat pups
Authors: Cahalan Kathleen J. , Graham Dee L. 
Published: January 2005

AbstractGunn rat dams were tested for differential retrieval of their jaundiced versus non‐jaundiced offspring in 2 experiments. In Experiment 1, in which testing took place every day from Day 1 to Day 8 postpartum, non‐jaundiced pups were retrieved significantly faster than jaundiced pups. In Experiment 2, in which testing took place every other day from Day 1 to Day 15 and the pups were weighed each test day, the order of retrieval of the 4 gender/genotype (jaundiced vs non‐jaundiced) classifications as found in the 1st experiment was replicated and the non‐jaundiced pups tended to be retrieved faster. Heavier pups were retrieved significantly faster than lighter pups, indicating that weight or size may be a cue to differential retrieval.
The interrelationship between thermal and olfactory stimulation in the development of home orientation in newborn kittens
Authors: Freeman Natalie C. G. , Rosenblatt Jay S. 
Published: January 2005

AbstractThe presence of a thermal gradient in the home cage and its use in home orientation was studied in kittens from shortly after birth to 2 weeks. Responses on a thermal gradient outside the home cage were also studied. With the home region and a freshly washed cage floor either cooled or warmed, kittens were placed in the adjacent corner or the home. In one study kittens chose between a cooled home and a warmed diagonal region. On a thermal gradient kittens exhibited thermotaxic turning and thermokinetic response. Kittens initially used either thermal or olfactory cues to reach the home but began to use only olfactory cues towards the end of the 1st week. Similarly, warmth in the home region caused “settling” during the 1st week but thereafter warmth and olfactory cues were most effective. Kittens chose the cooled home region more often than the warmed diagonal corner responding to olfactory over thermal cues.
Changes in cortical dendritic branching subsequent to partial social isolation in stumptailed monkeys
Authors: Struble Robert G. , Riesen Austin H. 
Published: January 2005

AbstractStumptailed monkeys were reared from 1 week after birth to 6 months of age in either a colony condition with the mother or in partial social isolation that allowed visual contact with the colony animals, but not physical contact. At 6 months of age the animals were killed and selected areas of the neocortex stained by the Golgi‐Cox method. Relatively nonspiney cells of Layer IV were drawn and analyzed for complexity of dendritic branching. Isolation‐reared animals had significantly decreased branching complexity in Motor I cortex when compared to the control animals. A transform of the data that related the number of branches to the number of previous branches showed a slight rearing effect in Somatosensory I cortex with the deprived animals having a lower rate of branching than the controls. We conclude that social isolation also includes a motoric deprivation that could account for these data.
Ultrasonic vocalization during social interaction and isolation in 2‐week‐old rats
Authors: Hofer Myron A. , Shair Harry 
Published: January 2005

AbstractTwo‐week‐old rats were found to emit very little ultrasound in their cage except during arrivals and departures of the mother, when average peak rates of approximately 1 ultrasonic pulse/rat/min were detected. However, when all pups except one were removed from the home cage, the remaining isolated pup emitted ultrasound at a mean rate of 12 pulses/min for at least 30 min. When young rats of this age were placed alone in an unfamiliar test area, the ultrasound pulse rate was approximately 25/min, whereas groups of 4 littermates in the same situation emitted only occasional ultrasonic pulses. If an isolated pup in the novel environment was allowed access to a single anesthetized littermate or mother this also significantly reduced the rate of ultrasound emission, whereas a warm clay model did not.
Comparative studies of the ultrasonic calls of infant murid rodents
Authors: Sales Gillian D. , Smith Jane C. 
Published: January 2005

AbstractThe ultrasonic calls of 10 species of murid rodents including 3 strains of house mice are described and the significance of interspecific similarities and differences is discussed. The calls of newborn murid rodents may be characterized by their gradual onset and cessation, their comparative lack of amplitude and frequency modulation, and, often, by the presence of only 1 frequency component. These common acoustic characteristics may be important in eliciting and/or maintaining various aspects of maternal behavior, both in and out of the nest.
Ontogenetic development of pentobarbital‐induced EEG pattern and sleeping time in rats
Authors: Staudacherová Dana , Mareš Pavel , Trojan Stanislav 
Published: January 2005

AbstractThe latency of onset and the duration of sleep induced by pentobarbital was studied in rats from 9 to 35 days of age, as well as in adult rats. Sleep latency was prolonged and sleep duration shortened with increasing age and maturation. Electrocorticographic changes after pentobarbital administration were studied in rats of 5–45 days of age and in adult rats. In rats 9 days of age or less the electrocorticogram manifested only depression of activity, whereas from the 12th day onward all characteristic barbiturate‐induced phenomena were registered: spindles, slow waves, and isolated spikes with suppression of background activity. Spindles were the most conspicuous of the pentobarbital‐induced phenomena and were the 1st to appear as a function of age, occurring only in the frontal areas at 12 days of age but in both frontal and occipital areas at 15 days of age. Frequency of the elements comprising spindles increased with from 2.5–3.5 c/sec in 12‐day‐old rats to 5–10 c/sec in adult animals. Barbiturate spindles could be used as a model for rhythmic thalamocortical phenomena even at early stages of development.
Contrast effects in the rat: A developmental study
Authors: Fagen Jeffrey W. , Shoemaker Gary E. 
Published: January 2005

AbstractTwo experiments investigated the exhibition and development of positive and negative contrast effects in the consummatory behavior of juvenile and adult rats. Over a 4‐day session, animals were given alternating 30‐sec presentations of 2 bottles containing either 32 or 4% sucrose solutions. In Experiment I, different groups of rats were tested both cross‐sectionally and longitudinally using a cohort‐sequential design. Cross‐sectionally, animals at all ages exhibited both types of contrast and demonstrated increasing positive contrast effects with greater age. Discrepancies between the longitudinal and cross‐sectional samples were found to be due to the repeated testing procedure of the former design. Experiment II replicated the positive and negative contrast effects in the juvenile animals, indicating that the processes responsible for contrast effects are operating in the rat at a very early age.
Developmental and genotypic effects on pituitary‐adrenal function and alcohol tolerance in mice
Authors: Swanberg Karen M. , Wilson James R. , Kalisker Albert 
Published: January 2005

AbstractLactating females of 2 lines of mice selectively bred for long (LS) and short (SS) ethanol‐induced sleep time (a measure of alcohol tolerance) consumed either tap water or 10% ethanol in tap water on Days 2–14 postpartum. Effects of genotype and neonatal treatment on offspring open‐field behavior, alcohol‐induced sleep time, and adrenocortical responsiveness to alcohol or saline injection were studied. The LS mice had higher ethanol‐induced sleep times than SS mice, and also higher plasma corticosterone levels following alcohol challenge. The LS mice also responded more to saline injection and to novelty stress, suggesting that they were generally more responsive to stressors than SS mice. Significant genotype‐dependent effects of neonatal treatment on (1) adrenocortical responsiveness to injection stress and (2) alcohol tolerance were noted. However, these 2 effects did not appear to be causally related. Neonatal treatment had no effect on open‐field activity or defecation in either genetic line.
Three parameters affecting interlitter variations
Authors: Woods Verne E. , Epstein H. T. 
Published: January 2005

AbstractWe studied 3 parameters affecting average body weight differences between mouse litters and have arrived at an approximation of the contribution that each makes to such differences. These parameters are birth weight, genetically based growth potential variations, and maternal competence. We have developed methods for controlling these parameters and show that through their application we can reduce litter‐average body weight differences from our normal value of more than 24% to about 3%. The vanished 21% consists of 12% due to differences in maternal competence, 6% due to growth potential differences, and 3% due to initial weight differences.
Do 16‐week‐old infants anticipate stimulus offsets?
Authors: Brooks Peggy R. , Berg W. Keith 
Published: January 2005

AbstractTwenty alert 16‐week‐old infants were presented with 20‐sec tones at variable intertrial intervals for 10 trials while beat‐by‐beat heart rate responses were recorded to assess response at offset as well as onset of each stimulus. Consistent with past research, onsets elicited deceleratory responses which habituated and showed some evidence of dishabituation with a change in stimulus frequency on the last 2 trials. Offsets also elicited significant deceleratory responses overall, but inspection of pre‐offset heart rate suggested that deceleration in anticipation of the offset event appeared after a few stimulus repetitions and increased in magnitude over trials. However, individual variability was considerable and although the anticipatory response was significant averaged over all trials, the apparent increase over trials did not reach statistical significance. The evidence clearly indicates infants quickly process and act upon temporal information in a stimulus.
Auditory evoked potentials and auditory behavior following prenatal and perinatal asphyxia in rhesus monkeys
Authors: Mirsky Allan F. , Orren Merle M. , Stanton Linda , Fullerton Barbara C. , Harris Sandra , Myers Ronald E. 
Published: January 2005

AbstractTwo types of asphyxia were studied in monkeys, total asphyxia during mid‐pregnancy (94–98 days gestation) and combined partial and total asphyxia at term (165 days gestation). Auditory evoked potentials and the acquisition of 2 auditory discrimination tasks were studied in asphyxiated animals as well as in a group of controls. The brains of all asphyxiates were examined histologically. No auditory discrimination deficit was found in the asphyxiated animals; however, the auditory evoked potentials differentiated between control and asphyxiated animals, especially those with verified inferior colliculus damage.
Plasma corticosterone response to serotonin altering drugs in the 3‐day‐old rat
Authors: Grota Lee J. 
Published: January 2005

AbstractThree‐day‐old rats were injected with various neurotransmitter altering agents to demonstrate a functional relationship between these drugs and plasma corticoid levels. Plasma corticosterone levels were increased after injection of methiothepin, methysergide, and 5‐hydroxytryptophan (5‐HTP), but were not changed by cholinergic, adrenergic, and dopaminergic compounds. Imipramine alone had no effects on plasma corticoids but in combination with 5‐HTP resulted in a more sustained response than 5‐HTP alone. A functional relationship between plasma corticosterone and serotonin receptors has been demonstrated in the 3‐day‐old rat. The presence of this relationship just after birth suggests the possibility that serotonin may be a mediator of early experience effects on later adrenocortical function.