Animal behavioral methods in neurotoxicity assessment: SGOMSEC joint report.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
E Alleva
Publications and source records attributed to E Alleva.
Appropriate end points for the characterization of behavioral changes in developmental toxicology.
The present paper is devoted to second- and higher-tier test methods for the characterization of behavioral changes produced in rodents by exposure to noxious agents during development. The paper analyzes a series of end points that are informative about specific processes and underlying regulatory mechanisms but require greater technical sophistication and larger investments than first-tier end points. This applies to ultrasonic emissions in successive postnatal periods; to mother-pup interactions, including appropriate cross-fostering controls; to social (including sexual) interaction tests from the infantile to the young adult stage; and to a variety of conditioning and learning tests using both positive and negative reinforcement.
Animals↗
Developmental exposure to ozone induces subtle changes in swimming navigation of adult mice.
Following exposure to ozone (O3, 0.6 ppm) from the beginning of neonatal life until weaning, adult CD-1 mice were tested in swimming navigation, a sensitive indicator for hippocampal damage. Control mice received a sham exposure. All mice were tested at 12-13 weeks of age for their ability to find a submerged platform in a fixed location (acquisition: 18 trials, six trials per day) and for capacity to re-orient towards a new platform position (reversal: 12 trials, six trials per day). Exposure to O3 did not produce any significant impairment of swimming navigation during the acquisition phase while it slightly increased the swimming paths during the last day of the reversal phase. Mice exposed to O3 showed a slightly but significantly higher swimming speed during all the days, which was unrelated to differences in body weight and to navigational performances. Moreover, mice exposed to O3 (with the exception of one animal) had a strong tendency to make turns to the left while the controls, independent of sex, preferred clockwise turns. Data are discussed with respect to possible implications with early CNS and immune alteration leading to behavioral asymmetries at adulthood.
Animals↗
Neuronal growth factors, neurotrophins and memory deficiency.
CNS and PNS ontogenesis are regulated by various proteic factors, and the best characterized of which still remains Nerve Growth Factor (NGF), a molecule exerting trophic, tropic (i.e. directing growing axons toward NGF-releasing target tissue) and differentiative effects on a number of neural and non-neural (e.g. mast-cells) cell lines. Other Growth Factors (GFs), called 'neurotrophins' (BDNF, NT-3, NT-4, NT-5) also exert similar effects on specific neural cell population. Other GFs (EGF, TGFs, IGFs, FGFs) share these growth-promoting properties with the neurotrophins. NGF appears to regulate specifically the postnatal maturation of the CNS cholinergics in altricial rodents. In adults, cholinergic neurons show retrograde transport for NGF and degeneration of cholinergic neurons after fimbria-fornix transection is prevented by NGF infusion, suggesting a role for NGF in maintaining normal cholinergic function in adulthood. However, peptidergic neurons (e.g. SP-positive cells) seem also to be influenced by perinatal NGF administration, indicating that the spectrum of NGF actions is wider than previously reported. In recent years we investigated the role of NGF in controlling behavioural maturation in the early postnatal period by comparing NGF effects with those of related and non-related neurotrophins (EGF, basic FGF, IGF-1, Transforming GF-alfa). We found that a single intracerebral injection of NGF accelerates cholinergic maturation on postnatal day (PND) 20, as shown by the enhanced reactivity to the muscarinic blocker scopolamine. Scopolamine-induced hyperactivity, normally appearing at the end of the third week, emerges already at PND 5 following NGF administration on PND 2 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Species specificity of organ toxicity: behavioral differences.
Explore the source record for details and available documents.
Animals↗
Limited changes of mouse maternal care after prenatal oxazepam: dissociation from pup-related stimulus perception.
There is evidence that activity at the GABA/benzodiazepine receptor complex in specific brain areas might be enhanced during rodent motherhood. We tested the hypothesis that the manipulation of this neurochemical system by prenatal benzodiazepine exposure affects typical behavioral responses of lactating mouse dams. Outbred CD-1 mouse fetuses were administered either oxazepam (OX, 15 mg/kg) or vehicle twice a day on embryonic days 12-16 and fostered at birth to untreated dams. Female offspring were subsequently mated at the young adult stage. In a first experiment, the behavioural repertoire of the two groups of lactating females was scored (single 10-min session) from postpartum days 3 to 18. When compared with VEH dams, OX females showed a shorter duration of pup-sniffing at 7-10 days and enhanced crouching behaviour when pups had reached the age of 14-18 days. In addition, OX-treated dams used more cotton for nest construction than the controls. The two female groups were differentiated only in the presence of their offspring. In a second experiment aimed at investigating possible OX-induced changes in pup-stimulus perception, the same lactating females were challenged in sequence on postpartum day 8 with three different patterns of pup-related cues consisting of: three 8-day-old live male pups (LP), three same-age dead pups DP, or three dead pups accompanied by pre-recorded ultrasounds (DPU). In the absence of carry-over effects of prenatal dam treatment, LP stimuli elicited a higher frequency of sniffing and digging than the others, whereas the level of licking, and grooming was reduced. In conclusion, the present results indicate that the slight alteration in maternal care resulting from prenatal OX treatment can be dissociated from changes in pup-related stimulus perception.
Animals↗
A comparison of behavioural effects of prenatally administered oxazepam in mice exposed to open-fields in the laboratory and the real world.
Prenatal benzodiazepine exposure has been reported to result in abnormal neurobehavioural development in laboratory animals but little is known about the behavioural relevance of this effect ina naturalistic environment. In this study, outbred CD-1 male mice were prenatally exposed to oxazepam (15 mg/kg per os, twice daily) on days 12-16 of fetal life and fostered at birth to untreated dams. At adulthood, each mouse was fitted with a radio collar and its first reactions assessed. Three hours later, behavioural and exploratory activities were recorded in a laboratory open field, and 24 h later in a natural setting. Immediate reactions to the radio collar were higher in the oxazepam-treated mice than in controls consisting of more attempts to remove it and an increase of push-digging. The attempts to remove the collar were still evident in oxazepam treated mice tested in the laboratory open-field 3 h later. Moreover, oxazepam increased the frequency of grooming and reduced walking in both the laboratory and the natural settings. In the natural settings running was increased during the initial 30-min test, while a pronounced level of grooming and a lower frequency of eating were observed 140 min after release. Frequency of sniffing, grooming, and rearing behaviours were higher in the laboratory test when compared to the natural settings. On the other hand, prolonged bouts of sniffing were recorded in the natural environment. These findings permit separation of robust drug effects (increased grooming, reduced walking) from situation-dependent effects, the natural environment revealing, in addition, more subtle effects.
Animals↗
Neurobehavioral development of CD-1 mice after combined gestational and postnatal exposure to ozone.
Outbred CD-1 mice were exposed continuously to ozone (O3, 0.6 ppm) from 6 days prior to the formation of breeding pairs to the time of weaning of the offspring on postnatal day 22 (PND 22) or to PND 26. One half of the mice in each of eight O3 and eight control litters were subjected on PND 24 to a 20-min open-field test after IP treatment by either saline or scopolamine (2 mg/kg). The remaining mice (those exposed until PND 26) were subjected on PNDs 28-31 to a conditioned place preference (CPP) test, using a short schedule with a single IP injection on PND 29 of either d-amphetamine (3.3 mg/kg) or saline. Subsequently, the saline mice of the open-field experiment were used on PND 59 for an activity test in one of the CPP apparatus compartments after IP treatment by either d-amphetamine (same dose) or saline. In addition, the saline mice of the CPP experiment underwent a multi-trial, step-through passive avoidance (PA) acquisition test on PND 59 or 60, followed 24 h later by a single-trial retention test. In the absence of effects on reproductive performance (proportion of successful pregnancies, litter size, offspring viability, and sex ratio), O3 offspring showed a long-lasting reduction in body weight without modification of sex differences. Ozone effects on neurobehavioral development were not large and quite selective, including: attenuation of the sex differences in several responses (rearing and sniffing in the open-field, activity in the final CPP test session); a change in response choices in the final CPP test, in the absence of a main effect on conditioning; a reduction of grooming in the activity test on PND 29; and impairment of PA acquisition limited to the initial period of training.
Amphetamine↗
Sibling effects on the behavior of infant mouse litters (Mus domesticus).
We investigated whether the number of same- or other-sex littermates had a graded effect on the occurrence of early solitary play and social play by mouse (Mus domesticus) family units. Sixty litters, reduced at birth to 5 different sex ratios (6 males, 5 males and 1 female, 3 males and 3 females, 1 male and 5 females, and 6 females) were scored in 15-min sessions on postnatal Days 18 and 21. An increasing trend with age was found for run, pounce, popcorn, self-groom, and explore episodes. Type of family unit influenced the occurrence of specific social interactions: One male-5 female and 6 female litters showed more social play than similar male litters. Litters with a balanced sex ratio showed higher exploration than isosexual litters. The results extend previous reports of both social and solitary play in developing laboratory mice and, in contrast with rat data, indicate a marked female primacy in playful social behavior.
Aging↗
Magnetic field effects on stress-induced analgesia in mice: modulation by light.
Exposure of adult male CD-1 mice to restraint stress for 60 min increased their hindpaw-licking latency in a hot-plate test (50 degrees C); this analgesia was significantly reduced after exposure to a stable magnetic field (MF) (30-40 G) under white light. In contrast, MF exposure under either red light or total darkness did not alter stress-induced analgesia. Results suggest that in rodents perception of magnetism might involve a light-dependent mechanism as recently found for migratory birds and amphibians.
Analgesia↗
Emotional stress induced by parachute jumping enhances blood nerve growth factor levels and the distribution of nerve growth factor receptors in lymphocytes.
We examined the plasma nerve growth factor (NGF) level and the distribution of NGF receptors in peripheral lymphocytes of young soldiers (mean age, 20-24 yr) experiencing the thrill of a novice about to make their first parachute jumps. Blood was collected from soldiers who knew they were selected to jump (n = 26), as well as from soldiers who knew they were not selected (n = 17, controls). The former group was sampled the evening before the jump and 20 min after landing. Compared with controls, NGF levels increased 84% in prejump and 107% in postjump sampling. Our studies also showed that the increase of NGF levels preceded the increase of plasma cortisol and adrenocorticotropic hormone. No changes in the baseline levels of circulating interleukin 1 beta or tumor necrosis factor were found, suggesting that the increased levels of NGF were not correlated with change in these cytokines. Moreover, immunofluorescence analysis demonstrated that parachuting stress enhances the distribution of low-affinity p75LNGFR and high-affinity p140trkA NGF receptors in circulating peripheral blood mononuclear cells. These observations suggest that the release of NGF might be involved in the activation of cells of the immune system and is most probably associated with homeostatic adaptive mechanisms, as previously shown for stressed rodents.
Adult↗
Impairment of passive avoidance learning following repeated administrations of antibodies against nerve growth factor in neonatal mice.
CD-1 Swiss mice were used to study the effects of repeated intracerebroventricular (i.c.v.) injections, on postnatal days (PND) 3, 6, 9, of rabbit antiserum (50 micrograms) raised against murine nerve growth factor (NGF) both on locomotor activity in an open field test (PND 10) and on a passive avoidance learning test (PND 11 and 12). While no difference was evident in locomotor activity levels between anti-NGF and control pups, an impairment of anti-NGF pups was detectable in the passive avoidance performance. Removal of endogenous NGF seems to produce a detrimental effect on a behavioural performance which is known to be under central cholinergic control, confirming previous reports on the role of NGF in early neurobehavioural responding in altricial rodents.
Acetylcholine↗
Early exposure to aluminium affects eight-arm maze performance and hippocampal nerve growth factor levels in adult mice.
Aluminium has been implicated in the etiology of several human pathologies but, to date, little attention has been given to the potential damage caused by gestational exposure to aluminium or to any long-term effect of early exposure. Aluminium sulphate (200 mg/kg) was administered intraperitoneally to pregnant female mice (days 10 to 13 of gestation), and male progeny was assessed in a radial eight-arm maze task at 70 days (20 daily sessions, 50 microliters water as reward). Overall, aluminium-exposed mice performed less efficiently in the radial maze than the vehicle-exposed animals. Neurobiological data showed that aluminium mice also had a higher level of nerve growth factor in the hippocampal formation when compared to controls.
Aluminum↗
Behavioral and hormonal responses to stress in the newborn mouse: effects of maternal deprivation and chlordiazepoxide.
These studies investigated behavioral and hormonal responses to stress in developing mice. Experiment 1 examined the effects of 24-hr maternal deprivation on corticosterone (CORT) secretion and ultrasonic vocalization (UVZ) rate in 4-, 8-, and 12-day-old mice. At these ages, exposure to a novel environment resulted in minimal changes in CORT secretion. Maternal deprivation increased pups' CORT secretion in an age-dependent fashion but did not affect their UVZ rate. The aim of experiment 2 was to test the effects of chlordiazepoxide (CDP), an anxiolytic compound, on CORT secretion and UVZ in both normally reared and in maternally deprived 8-day-old mice. CDP administration elevated CORT secretion in a dose-dependent fashion, producing larger CORT increases in deprived (DEP) animals. CDP affected UVZ only in nondeprived (NDEP) animals: UVZ rate was decreased by high CDP doses. Overall, these findings demonstrate that the infant mouse shows a period of stress hyporesponsiveness similar to the rat and that maternal presence contributes to inhibit adrenocortical activity. CDP administration, but not novelty exposure, increased CORT secretion in 8-day-old normally reared mice suggesting that during the stress hyporesponsive period, the HPA axis is capable of responding only to specific stimuli. Changes in HPA axis activity and UVZ rate resulting from maternal deprivation and/or CDP challenge do not seem to be directly related.
Animals↗
Limited effects of ozone exposure during pregnancy on physical and neurobehavioral development of CD-1 mice.
Only a few studies have attempted to assess in laboratory rodents the maternal toxicity and behavioral changes in offspring caused by prenatal exposure to ozone (O3). In particular, no data are available concerning the behavioral development of mouse offspring after maternal exposure, despite the fact that increasing use is made of this species in behavioral teratology studies for reasons both of economy and in order to increase the effectiveness of subsequent higher-tier studies (e.g., of treatment-genotype interactions). In the present work, female CD-1 mice were exposed during pregnancy (Days 7-17) to different O3 concentrations (0, 0.4, 0.8, or 1.2 ppm); to avoid confounding by postnatal maternal effects, all litters were assigned shortly after birth to foster dams neither treated nor handled during pregnancy. The dams' food and water intake and body weight gain were depressed in a concentration-dependent fashion. Tolerance to these effects developed during continuing exposure; such tolerance was faster in the case of food than water intake. Several measures of reproductive performance, such as proportion of pregnancies carried to term, litter size, sex ratio, frequency of stillbirth, and neonatal mortality, failed to show differences between control and O3 animals. Postnatal body weight gain was slightly but significantly depressed in the 1.2 ppm offspring. Otherwise, the somatic development of O3 pups was indistinguishable from that of controls, save for a delay in eye opening; this effect, however, failed to show a significant concentration dependence. Negative results were obtained in a wide range of assessments concerning (i) the development of various reflexes and responses ("Fox battery") from birth to Day 18; (ii) ultrasonic emissions on Postnatal Days 3, 7, and 11; and (iii) activity, habituation, response to an unfamiliar object, and hyperactivity produced by a monoaminergic stimulant (d-amphetamine) at 60-61 days. The present data differ from those of a previous study on rats raised by their biological mothers after gestational exposure to O3 (1 and 1.5 ppm), which showed a substantial impairment in somatic and neurobehavioral development (R. Kavlock, E. Meyer, and C. T. Grabowski, 1980, Toxicol. Lett. 5, 3-9). This difference, be it due to species factors, to postnatal maternal effects, or to the time of occurrence of maximal O3 effects (e.g., on food and water intake) after the onset of exposure and before adaptation or tolerance, may provide significant cues for the understanding of O3 effects in pregnant and developing organisms.
Animals↗
Prenatal cocaine potentiates the effects of morphine in adult mice.
Prenatal cocaine exposure has been reported to result in abnormal neurobehavioral development, both in animals and humans. In this study, outbred CD-1 mice were exposed in utero to cocaine hydrochloride administered daily as i.p. injections to dams from day 10 of gestation to day 16, at the dose 0, 5 or 50 mg/kg. Cocaine did not alter duration of pregnancy while it decreased the difference in maternal body weight from days 10 to 16 in the dams receiving the higher dose of cocaine. The body weight of the offspring from birth to 15 days of age and the physical maturation were not affected by prenatal cocaine exposure. The development of the response to strong tactile stimulation was either slightly delayed in the 5 mg/kg group or markedly accelerated in the 50 mg/kg group. At adulthood, animals were assessed for behavioral responses to a novel environment, for response to painful stimulation (hot-plate test set at 55 +/- 1 degree C), and for the effects of a single morphine injection (30 mg/kg, i.p.). Data showed that in the absence of prenatal cocaine exposure effects, morphine increased the time spent in inactivity, while it decreased rearing, grooming and bar-holding behaviors. In the case of sniffing, morphine increased this behavior, except in the 5 mg/kg cocaine group. Moreover, morphine administration induced the expected increase of locomotion, irrespective of prenatal condition. With respect to pain reactivity, prenatal cocaine exposure resulted in an increase of licking latency in the 5 mg/kg group.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Removal of the submaxillary salivary glands first increases and then abolishes the agonistic response of male mice in repeated social encounters.
Adult male mice of the CD-1 strain were sialectomized (bilateral removal of submaxillary salivary glands) under IP Nembutal anesthesia and then individually housed for 5 weeks. Control mice were sham operated. The behaviors of sialectomized and control mice towards untreated, intact, matched opponents were videotaped during the first 10 min of a 20-min social encounter repeated for 10 consecutive days (isolation days 36-46). On the first session, sialectomized mice exhibited significant increases in elements of aggression (attack, bite, offensive sideways, offensive upright, and tail rattling). These behavioral changes significantly decreased over the remaining encounters, while defensive behaviors (defensive upright, oblique, parry, and defensive sideways) and elements of arrested flight increased progressively. The results suggest that sialectomy, perhaps by removing salivary NGF, interferes with the coping response of mice towards repeated agonist challenge from a conspecific.
Adaptation, Psychological↗
Snake odor alters behavior, but not pain sensitivity in mice.
It is known that predator cues (both mammalian odor or avian vocalization) elicit marked analgesia in rodents. The present experiment used olfactory cues produced by an opportunistic rodent predator snake species (100 cc of sawdust scented by Elaphe quatuorlineata). Upon exposure to snake odor (for 30 s, 20 min, or 40 min), adult mice of both the CD-1 and DBA2 strains were assessed for tail-flick or hot-plate analgesia at different times after exposure (from 0 to 40 or 45 min, respectively). In both strains, snake odor exposure induced significant alteration in the frequencies of sniffing, self-grooming, and digging, while it inhibited habituation of locomotor activity in DBA/2 mice. No analgesia emerged with both tests as a consequence of exposure to snake odor. Results suggest that although endogenous analgesia has been demonstrated by other authors to be elicited in response to cues emanating from common and widely distributed mouse predators (such as carnivores or owls), predators such as reptiles, which under natural conditions exert a limited predatory pressure on the house mouse gene pool, may only induce fear-associated behavioral responses but cannot provide ethologically relevant stimuli triggering mouse analgesia.
Animals↗