Stata Norton

Locomotor damage in rats after X-irradiation in utero

Abstract Alterations in gait were found in rats after whole-body irradiation with 125 r on day 14, 15, and 16 of gestation. No effects on locomotion were detected after irradiation on day 17 with 125 r or after irradiation on day 14 with 50 r. A technique was set up for quantitative evaluation of locomotion based on a modification of other methods. Walking patterns of irradiated rats were recorded, when they were adults, by requiring them to walk up a 10° incline through a corridor after their feet had been dipped in ink. Rats irradiated on gestational day 14 had an in-phase, hopping gait with the sine of the angle between the hind feet and the direction of progression over 0.9. Rats irradiated on gestational days 15 and 16 had an alternating, waddling gait with wider stance and broader angle than control rats. Histologic examination of serial sections of the brains of these rats showed that the 14-day rats lacked all telencephalic commissures except for a few fibers which crossed in some rats. There was a progressive improvement in the condition of the anterior and ventral hippocampal commissures up to day 17, but the corpus callosum and dorsal hippocampal commissure were lacking or markedly reduced in all day 17 rats. No animals showed damage to the mesencephalic posterior commissure. Since rats which used the in-phase mode of locomotion were never observed to use alternating gait, the possible causal relationship of the commissural damage to the altered locomotor patterns was considered. In view of the restricted period of damage found for the anterior and ventral hippocampal commissures and the restriction of altered locomotion to damage in the same period, primary involvement of the corpus callosum and dorsal hippocampal commissure could be excluded, but a possible role for the other telencephalic commissures remained.

Effects of perinatal methimazole exposure on a developmental test battery for neurobehavioral toxicity in rats

Abstract The antithyroid drug, methimazole, was investigated to assess its potential as a positive control agent in developmental behavioral studies. Methimazole was administered in drinking water to dams from the 17th gestational day to the 10th postnatal day. Methimazole treatment produced developmental delays and motor deficits in offspring tested in a behavioral battery assessing development of sensory and motor function. Acquisition of a righting response was delayed 7 days, from postnatal Day 7 in controls to Day 14 in treated rats; the appearance of the auditory startle response was delayed 6 days, from Day 12 to Day 18; the time of eye opening was delayed 2 days, from Day 15 to Day 17. A deficit, rather than a delay, was observed in body weight gain and in a reflex-suspension test of motor development. Treated rats showed decreased exploratory activity in an open field at postnatal Day 21 compared with controls. It was concluded that developmental test batteries, such as those proposed to screen for neurobehavioral toxicity, may readily detect neurotoxic damage from goitrogens. The convenience of methimazole administration in drinking water plus the efficacy of methimazole inducing developmental deficits and delays suggests this agent may be an effective positive control in developmental behavioral test batteries.

Circadian and sex differences in hyperactivity produced by amphetamine in rats.

Abstract Hyperactivity produced in rats with d-amphetamine HCl was measured using a residential maze. Groups of 4 male or 4 female rats were kept on a 12-hr light, 12-hr dark schedule. Amphetamine was given 4 hr after onset of either the light or dark cycle and activity measured for the following 8 hr. For all doses of amphetamine (in light or dark), females displayed significantly greater increases over control activity than males. The results suggested that the greater activity of female rats was not due solely to the recognized sex difference in amphetamine metabolism, but rather there was a sex-related difference in the CNS. Previous experiments have shown that neonatal asphyxia and x-irradiation in utero produce greater hyperactivity in female than in male rats. It is proposed that female rats are more likely to develop hyperactive behavior.

Development of nocturnal behavior in albino rats.

When the activity of groups of rats is monitored in a residential maze equipped with photocells for recording passage through the corridors, rats can be shown to be more active in the 12-hr dark portion of a day than in the 12-hr light portion from an early age. Groups of rats weaned at 23 days of age show significantly greater activity at night than during the day but the maximum nocturnal/diurnal ratio is recorded in young adult rats 2–4 months old. Although females older than 5 weeks are more active than males both during the light and dark cycle, the nocturnal/diurnal activity ratios show the same trends in the two sexes. Males differ from females in the duration of their exploratory activity when they are first introduced into the maze. Females are consistently much more active during the second hour in the maze but the differences between the sexes in activity during the first hour are not as great. The development of nocturnal activity of groups of rats in these experiments corresponds generally with results obtained on isolated rats, implying that social interaction is not a primary cause of the nocturnal activity recorded in these experiments.

Forebrain damage following prenatal exposure to low-dose X-irradiation.

Exposure of fetal rats to X-irradiation on gestational day 15 resulted postnatally in dose-related effects on body weight, growth of forebrain structures, and branching of dendrites of caudate neurons. Rats were followed for 4 months postnatally after 125, 75, 50, or 25 R whole-body irradiation to the dam. Significant decreases in body weight were present at birth after the three high doses and continued as long as 4 months after 125 or 75 R. Decreased thickness of the cerebral cortex and decreased area of the caudate nucleus were also seen. Cortical thickness was reduced by 125 R to half the size of the control cortex and the caudate nucleus to two-thirds of the control. Significant decreases were present to 50 R. Dendritic branching was reduced in caudate neurons by 125 R but not in the basilar dendrites of cortical pyramidal cells. No reduction in number of cortical synapses was seen from electron micrographs of cortical layers 1 or 5. The effect on the cerebral cortex was interpreted as a loss of neurons with retention of branching and synaptogenesis of remaining neurons. In contrast, the caudate nucleus, which develops somewhat before the cerebral cortex, showed effects as a consequence either of direct damage to caudate neurons or of reduced neuropil from reduced afferent input.

Behavioral consequences of perinatal hypothyrodism in postnatal and adult rats

The long-term effects of perinatal hypothyroidism on spontaneous locomotor behaviors were assessed after exposure to the antithyroid drug, methimazole. Perseveration was observed in methimazole-treated rats in a spatial maze. Locomotor activity in residential mazes was examined at 6 weeks, 4 months, and 6 months of age. Treated rats were hypoactive at some intervals compared with controls and were hyperactive at others. These paradoxical differences resulted from changes in exploratory, diurnal, and nocturnal locomotor activity in control rats both with increasing age and on repeated exposures to residential mazes; rats after perinatal hypothyroidism had relatively constant levels of activity on repeated days of exposure to residential mazes and at different ages. These results may be related to perseveration noted in the spatial maze. In an analysis of walking patterns, treated rats tended to have a more pronounced asymmetry in gait than controls.

Hyperactive behavior of rats after lesions of the globus pallidus

Following bilateral lesions of the globus pallidus, rats living in a residential maze were hyperactive during the 12 hr dark cycle but not during the 12 hr light cycle. Lesioned rats were less exploratory during the light cycle than control rats but not during the dark cycle. Exploratory behavior of rats was photographed for 15 min during the light cycle. The duration of 6 behavior acts was significantly shorter than controls (scratching, grooming, sitting, sniffing, standing and rearing). The number of initiations of grooming, scratching, sniffing and smelling decreased while looking and walking increased in frequency. The linkage of behavior acts into sequences was diminished compared with controls. Similar, but not identical, changes were found when the structure of exploratory behavior of naive rats was compared with the exploratory behavior of experienced rats. It is concluded that naive control rats are hyperactive relative to experienced rats in this exploratory situation and that rats with pallidal lesions display changes in their behavior which are characteristic of hyperactive animals even when other tests under similar conditions, such as exploration during the light cycle in a maze, show the pallidal rats as hypoactive relative to control rats.

Development of opiate tolerance in the chick embyro

Tolerance to morphine was produced in the chick embryo. Eggs were injected with morphine sulfate (MS) (20 mg/kg egg) or H2O daily starting on incubation day 12. On day 16, embryo activities were recorded and eggs were injected with either MS or naloxone. Activity of H2O-pretreated controls decreased after both MS and naloxone. Embryos treated with MS from incubation days 12-15 showed no activity change after morphine and responded to naloxone with increases in activity. Baseline rates of distress vocalizations (DV) of 1-2 day old chicks were not affected by MS pretreatment during incubation days 12-19. However, 1 mg/kg MS decreased the rate of DV of control chicks by 90% whereas MS-pretreated chicks were unaffected. At age 4-5 days, the baseline rate of DV and rate after MS were higher in MS-pretreated chicks. However, all chicks showed significant decreases in rate of DV after MS injection. Naloxone increased the rate of DV of paired 1-2 day old chicks, but response of MS-pretreated chicks was significantly greater than controls.

Caudate morphology and behavior of rats exposed to carbon monoxide in utero

Postnatal morphologic damage was found in the caudate nucleus of rats exposed 2 or 3 h to carbon monoxide on gestational day 15. There were gross abnormalities in the form of ecotopic swellings of caudate tissue into the lateral ventricles. The incidence of caudate ectopias was about 20% in rats exposed 2 h as fetuses and 70% from 3 h of exposure. In addition, in the body of the caudate the number of dendritic branches was reduced in Golgi type II neurons. Postnatal behavior of the exposed rats was not significantly altered in a series of behavioral tests of motor function. Growth rate was not retarded. The failure to detect behavioral changes may be due to insensitivity of these tests detecting functional damage or to compensation by the developing brain, resulting in normal function.

Morphological damage to the premature fetal rat brain after acute carbon monoxide exposure

Abstract On gestational day 15 pregnant female rats were exposed 3 h to carbon monoxide (CO) in a dynamic flow chamber. The concentration of CO was approximately 0.1% in filtered air and maternal carboxyhemoglobin attained 50% during the exposure. Rat fetuses were taken by cesarean section on gestational day 16, 24 h after the exposure, for histological evaluation of the central nervous system. The ventral germinal matrix overlying the developing caudate nucleus was the region most consistently and severely damaged by CO exposure. Hemorrhagic infarcts with necrosis in this germinal matrix and cavities with cellular debris were characteristic observations in the developing caudate of CO-exposed fetuses. In contrast, the dorsal germinal matrix of the neopallium was not damaged by CO exposure. The ventral germinal matrix was less well vascularized and more developed than the dorsal region at this gestational age. The findings suggest that the combination of limited vascularity and high proliferative activity, characteristic of the germinal matrix of the developing caudate at this stage, can explain the selective vulnerability to hypoxic damage. The pattern of damage seen in our rats was similar to the deep periventricular pattern of brain damage observed in premature human newborns after acute hypoxic episodes.