Groups (G) of pregnant rats were gavaged with 1:1, 2,4-D/2, 4, 5-T mixture at 0 (GO), 50 (G50), 100 (G100) and 125 (G125) mg/day on gestational days 6 to 15. G100 and G125 dams gained significantly less weight during pregnancy and delivered fewer offspring than control. Gestational lengths, neonatal sex ratios, birth weights, and physical appearance at birth were unaffected by treatments. On postnatal day (PND) 1, G125 mortality was significantly increased. Except for a significant weight reduction in G125 on PND60, postnatal growth and maturation were unaffected by treatments. 2,4-D/2, 4, 5-T significantly delayed male and female surface righting (PND2-5), and negative geotaxis at 45 degrees angle (PND15-17) in all groups; olfactory discrimination (PND9-11), and negative geotaxis at 25 degrees (PND7-11) in G100 and G125. On PND9 negative geotaxis at 25 degrees were significantly delayed in G50 females. d-Amphetamine challenges significantly increased running wheel activity of G125 males on PND22 and 23. 2,4-D/2,4,5-T was behaviorally teratogenic at all dosage levels.
Male rats were chronically treated via drinking water with 50 or 500 ppm sodium acetate or 50 or 500 ppm lead acetate from weaning. Behavioral testing on a fixed-ratio (FR) schedule of reinforcement began at 55 days of age. A series of increasing ratio values was studied. The lower exposure level was without effect at any ratio value. The 500 ppm concentration decreased response rates over the first 15-20 sessions of FR5 and FR25, after which rates reached control levels. Changes in response rate derived primarily from longer interresponse times (IRTs) and decreased running rates. Differences in performance were not evident at FR values of 50 and 100. The 50 ppm concentration produced blood lead (PbB) values averaging 30.3 micrograms/dl; the 500 ppm concentration produced PbBs of 58-94 micrograms/dl. Zinc protoporphyrin levels resulting from 500 ppm exposure differed from controls even after one month of exposure, and continued to increase over eight months of exposure, to 72 micrograms/dl. Comparison of these data to previous studies from this laboratory of FI performance in which the identical exposure protocol was employed, suggests that FR response rates are less sensitive than FI to disruption by lead.
Mexiletine, an antiarrhythmic drug, exerted a protective effect in mice against convulsive seizures induced by electroshock or the chemical convulsant, pentylenetetrazol, and against seizures induced in inbred audiosusceptible mice by a sound signal. Administered in large doses, mexiletine produced a hyperkinetic myoclonic syndrome of 30-60 min duration. The hyperkinesia could be controlled by dimethylaminoethanol, phenobarbital and by an experimental anticonvulsive agent, eboracin.
The possibility that dietary exposure to triphenyl phosphate (TPP) may result in detectable neuromotor dysfunction was investigated. Young male Sprague-Dawley rats were fed diets containing TPP at levels of 0, 0.25, 0.50, 0.75 or 1.0% for 4 months. At approximately monthly intervals, a battery of behavioral tests was administered to assess different facets of neuromotor function including motility, balance, coordination and muscular strength. Treatment-related decrements in growth, in the absence of changes in food consumption, were found at all dietary levels above 0.25%. However, none of the behavioral measures used in this study were affected by the dietary treatment. It was concluded that there is no evidence of neuromotor toxicity following subchronic dietary exposure to TPP in the rat.
Peripheral nerve conduction time and parameters of potentials evoked from brain by somatosensory, auditory, and visual stimulation were studied as a function of the concentration of carbon disulfide (CS2) chronically inhaled by female Long-Evans rats. Thirty rats were divided into three groups of ten each and exposed to air or 400 or 800 ppm CS2 7 hours per day, 7 days per week, for 11 weeks. Stimuli consisted of tail shock, clicks, tone pips, light flashes, and reversing visual patterns to evoke multisensory potentials. Effects were observed on conduction time in the periphery, in brainstem auditory pathways and in the visual system. The effects on pattern-reversal potentials were greater than those on flash-evoked potentials.
This report is one phase of a longitudinal prospective study on the behavioral teratology of alcohol. The present study evaluated the effect of early prenatal alcohol exposure (assessed during pregnancy) on reaction time, attention and distraction in 475 young school-age children who took a computerized CPT vigilance task. Multiple regression analyses were adjusted for a variety of co-variates including other exposures, postnatal conditions and demographics. Prenatal alcohol exposure was most significantly related to CPT errors of commission, reaction time, and the vigilance errors summary score. Error scores on the vigilance task were also significantly correlated with independent behavior ratings of endurance, persistence, organization, distractibility and impulsivity. This study supports and extends earlier reports of alcohol-related attentional deficits observable in the neonatal period and in the preschool years.
There was no evidence of peripheral neuropathy or other neurotoxicity in rats dermally treated with a 12% aqueous solution of the amine salt of 2,4-dichlorophenoxyacetic acid (2,4-D amine). Male and female Fischer 344 rats were treated on the skin of all four limbs with 2,4-D amine for 2 hr/day, 5 days/week, for 3 weeks. Measurements were: body weights, hindlimb grip strength, accelerating rod performance, single and paired pulse electrophysiology of the caudal and sciatic nerves, hindfoot H-reflexes, light microscopy of brain, spinal cord, sciatic nerve, tibial nerve, digital nerve, and electron microscopy of the tibial nerve. The experiment continued for up to one month postexposure. Treatment caused a weight loss in both male and female rats and caused minor skin changes during treatment in both sexes. No other treatment-related effects were found.
When pregnant rats were X-irradiated at a dose of 100 R on gestational day 9.5, a considerable number of postnatally-viable hydrocephalic offspring resulted, all of which were accompanied with bilateral micro- or anophthalmia. Histological studies revealed that the cerebral aqueduct of the congenital hydrocephalic brain was severely stenosed, and the subcommissural organ was reduced in size and displaced at some distance from the anterior end of the cerebral aqueduct. From embryological studies, it was considered that the maldevelopment of the subcommissural organ in the X-irradiated fetus might cause a reduction in the amount of its secretions which function as a cushion preventing complete closure of the cerebral aqueduct during fetal life, resulting in stenosis of the cerebral aqueduct.
Treatment of neonatal mice with large, repeated doses of monosodium L-glutamate (MSG) produces a syndrome of obesity and endocrinological dysfunction generally attributed to a hypothalamic lesion. We have used single injections of MSG, administered on postnatal day four, to explore the lower end of the dose-response curve for this toxin. Major features of the MSG syndrome including hypophagia, obesity, hypoactivity, reduced pituitary protein content, decreased ovarian weight, delayed puberty and elevated plasma corticosterone levels were obtained at the highest dose. Of the variables measured, feeding disturbances and reduced pituitary and ovarian weights were the most sensitive indicators of damage. The extent of damage produced in the arcuate nucleus of the hypothalamus increased with increasing dose. A prominent lesion was also detected in the medial preoptic area of animals receiving the highest dose. Damage was not evident in other diencephalic structures associated with body weight regulation. Since little is known about the mechanisms underlying MSG obesity, a second study examined the contribution of ovarian hormones to obesity in MSG treated mice. Ovariectomy increased the body weights of animals injected with low but not high doses of MSG, suggesting that a reduction in ovarian function may contribute to the MSG obesity syndrome in the female. Measurement of hypothalamic monoamines and metabolites in these mice indicated that as with repeated doses of MSG, single injections of the toxin reduced hypothalamic dopamine levels. DOPAC levels were unchanged.
The conditioned taste aversion procedure was used to further assess some behavioral effects of treatment with the putative radioprotectant WR-2721 and the role of the area postrema in mediating the behavioral effects of treatment. Treatment with 40, 150 or 300 mg/kg WR-2721 produced dose-dependent changes in sucrose intake in both control rats and rats with area postrema lesions. The effectiveness of the lesion in disrupting the acquisition of an aversion varied as a function of the dose administered, with the lesions producing the greatest disruption of aversion learning at the lowest dose and little disruption at the highest dose tested. At all dose levels, sucrose intake was greater for the rats with area postrema lesions than for the sham-operated control rats. Treatment with WR-2721 also produced significant decreases in total fluid intake, particularly at the higher dose levels. The results are discussed as indicating that treatment with WR-2721 produces highly toxic effects on behavior and that the use of the compound as a radioprotectant for radiotherapy requires additional assessment of its effects on brain function and behavior.
Inhalation exposure of rats to toluene causes irreversible hearing loss (e.g., Pryor et al.). To determine whether noise emanating from the inhalation system was a major contributing factor and whether exposure by a noninhalation route would cause a similar effect, weanling, male Fischer-344 rats were injected SC twice daily in a quiet environment with PEG-300 (control) or with 1.5 or 1.7 g/kg of toluene for 7 days. After being trained to perform a multisensory conditioned avoidance response (CAR) task, tone intensity-response functions were generated at 4, 8, 12, and 20 kHz, and behavioral auditory response thresholds were estimated. Toluene caused a dose-related hearing loss at frequencies of 8 kHz and above, with no effect on performance of the CAR in response to light, nonaversive footshock, or the 4-kHz tone. The similarity of this effect to that observed following inhalation exposure indicates that noise is not a major factor in the toluene-induced hearing loss, although possible interactions between noise and toluene remain to be investigated. These results also demonstrate that direct penetration of the toluene vapors through the external ear structure, as might occur during inhalation exposure, is not a necessary condition for inducing the hearing loss.
The majority of infants born to drug-dependent women undergo neonatal abstinence syndrome (NAS) and often require pharmacotherapy for the treatment of withdrawal symptoms. Phenobarbital, paregoric, and diazepam have been recommended for the treatment of the syndrome. While some investigators have examined the efficacy of these agents in treating NAS, there are no data regarding the use of specific pharmacologic agents and developmental outcome. This study evaluated 85 infants born to drug-dependent women who were maintained on methadone during pregnancy. Severity of infant withdrawal was assessed with the neonatal abstinence scoring system. Infants who required pharmacotherapy were randomly assigned to one of four treatment regimens: paragoric, phenobarbital (titration), phenobarbital (loading), and diazepam. When treatment was not successful with the assigned agent, one of the other agent(s) was used. At 6 months of age, the developmental status of infants was assessed with the Bayley Scales of Mental Development. Based on NAS treatment, four groups were defined: paregoric (n = 21); phenobarbital (n = 17); more than one agent (n = 31); and no treatment (n = 16). Data for the phenobarbital loading and titration groups were combined since analysis revealed no differences between groups. All infants who initially received diazepam were included in group III since diazepam as a single agent was not successful. Results of one way analysis of variance revealed no differences in developmental status between groups (p greater than 0.10, F = 0.25). Scores for all groups were well within the normal range of development.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of triethyl lead (TEL) on ingestive behavior in adult male rats was studied in two experiments. In experiment 1, ad lib food and water intakes were monitored following SC injection of 1, 4, or 7 mg/kg body weight of TEL or vehicle; both were significantly attenuated at 4 and 7 mg/kg doses. In a second experiment, the same doses of TEL were given SC in a conditioned taste aversion (CTA) paradigm. Following a single pairing, a dose-related reduction in intake of a 0.1% saccharin solution was observed at all doses tested. Sensitivity of behavioral measures and potential role of discomfort in TEL-induced feeding/drinking shifts were considered.
Rats were injected with saline, 1.0 mg/kg or 2.6 mg/kg of diisopropyl phosphorofluoridate (DFP). Three days later the animals were placed in cages in which they could press a lever to obtain their entire daily ration of food. The time of day at which responses occurred and the time between successive responses were recorded over a six day period to determine the circadian pattern of lever-pressing and the distribution of inter-response times (IRTs). The saline injected rats exhibited a normal nocturnal pattern of feeding, while both DFP treated groups exhibited a significantly greater tendency to eat during the day. Analysis of the IRT distributions of the three groups showed a different pattern of results. The saline and 1.0 mg/kg DFP groups produced nearly identical IRT distributions, while the 2.6 mg/kg group produced an IRT distribution which was marked by significant increases in the interquartile range and median IRT. Since the 1.0 mg/kg dose of DFP produced a circadian disruption but did not affect the IRT distribution, it appears that the disruption of circadian activity by DFP which was reported by Raslear and Kaufman cannot be solely explained by simple changes in the motor response.
Behavioral effects of a single exposure to toluene were investigated on 12 rats by means of a shock avoidance task in a shuttle box. After 10 days of acquisition training, 3 groups of 4 rats were exposed to toluene vapor for 4 hr at concentrations of 8,000, 4,000, and 2,000 ppm. The maintenance of shock avoidance and time estimation was examined immediately after, and at the 3rd and 6th hr after the 4 hr toluene exposure. No avoidance response occurred immediately after 8,000 ppm toluene exposure, but it was recovered by the 3rd hr after exposure. Both 4,000 and 2,000 ppm toluene exposures increased the percentage of avoidance response. The response latencies (RLs) were significantly shortened after toluene exposure and the relative frequency distribution of RLs was shifted toward a shorter RL. The shortening of RLs could be attributed not only to the excitatory effect of toluene but also to the acceleration of response initiation. It is possible that toluene-exposed rats estimated the time interval to be longer than the real time, and that this over-estimation of the time interval hastened the timing of response initiation.
Exposure of the mammalian fetus to ethanol causes a variety of nervous system abnormalities, but the evidence relating to seizure susceptibility is contradictory. Therefore, offspring of rat dams that had consumed a mean of 6.9 g/kg/day of ethanol were compared with pair-fed and free-fed controls on rate of electrical kindling of the amygdala and on open field measures of activity. The Ethanol-exposed males displayed increased ambulation and the Ethanol females displayed increased rearing and defecation in an open field. However, there was no significant difference between the groups in rate of kindling. Although the gross size of the brains measured on a coronal section through the anterior tip of the hippocampus did not differ significantly among the groups, there was a highly significant reduction in percent brain tissue area and a corresponding increase in percent ventricle area in the Ethanol group.
