Biomedical subjects

R R Holson

Publications and source records attributed to R R Holson.

63 records · Page 4Linked to original sources

PubMedDate not supplied

Neonatal dexamethasone on day 7 in rats causes behavioral alterations reflective of hippocampal, but not cerebellar, deficits.

Developmental glucocorticoid treatment in rats has been shown to cause body and brain weight decrements concurrent with behavioral alterations. Here, Sprague-Dawley rats were treated with the synthetic glucocorticoid, dexamethasone (DEX), on postnatal day (PND) 7 (1.5 mg/kg, sc, injected in the morning and afternoon). Behavioral assessments of negative geotaxis, locomotor activity (open field, maze exploration, residential running wheel, residential figure 8 maze), open-field activity response to amphetamine, acoustic startle, prepulse inhibition (PPI) of acoustic startle, juvenile play behavior, anxiety (emergence tests), motor coordination (rotarod performance), spatial learning (Morris water maze and food-reinforced complex maze), and operant performance (time estimation and response inhibition) were assessed in male rats. Body weight was decreased beginning at PND 43 until sacrifice on PND 127. Whole and regional brain weights were less, especially hippocampus, cerebellum, brainstem, and cortical remnant. Indications of delayed development were apparent; specifically, DEX-treated rats took significantly longer to turn on PND 8, but not PND 9, in the negative geotaxis test. DEX treatment induced deficits in the Morris water maze that were similar to hippocampal deficits. Open-field activity changes were inconsistent; however, DEX-treated rats were hyperactive during the dark period in running wheel tests. There were no indications of changes in reactivity or emotionality.

Amphetamine↗

PubMedDate not supplied

Gestational retinoic acid exposure in the rat: effects of sex, strain and exposure period.

Effects of gestational exposure to all-trans retinoic acid (RA) were assessed in the Long-Evans (hooded) and Sprague-Dawley (albino) rat strains. Two exposure periods were evaluated against vehicle controls. Both involved three consecutive daily per os doses of either 2.5 mg/kg RA on gestational days (GD) 11 through 13 or 10 mg/kg RA on GD 14 through 16. All assessments were conducted on at least one male and one female per litter. Substantial main effects of sex, strain and treatment were obtained, but with few significant interactions. Main effects of strain were found on surface righting, neonatal mortality, litter weight and postnatal day (PND) 35 regional brain weight. Among strain effects, the most interesting was the finding that weights of whole brain, frontal cortex, brainstem and cerebellar vermis were lower in hooded than in albino rats. These strain effects seldom interacted with treatment. Among the treatment effects was the finding that GD 11-13 but not GD 14-16 RA exposure impaired the righting reflex in both strains. Moreover, GD 11-13 exposure reduced weight of the cerebellar vermis more than did GD 14-16 RA exposure, while GD 14-16 RA exposure had greater impact on the weight of the cerebellar hemispheres than did GD 11-13 exposure. Covariate analysis suggested that these effects were independent of reductions in body weight. It is concluded that there are few strain or sex differences in the effects of gestational RA exposure, at least for the rat strains evaluated in this study.

Animals↗

PubMedDate not supplied

Gestational retinoic acid exposure: a sensitive period for effects on neonatal mortality and cerebellar development.

This is the first in a series of studies investigating the developmental stage-specific neurobehavioral effects of all-trans retinoic acid (RA) exposure. Because high doses of this compound are known to be lethal to the developing organism, we first conducted a dose-response study to identify RA doses that produce low enough levels of gestational/postnatal mortality to make a behavioral analysis possible in survivors. Secondarily, at doses found to produce sufficient survivors on PND 28, effects on body and regional brain weights were examined. Finally, at these doses, effects on somatic malformations were evaluated. Four separate exposure periods were analyzed: gestational days (GD) 8 through 10, 11 through 13, 14 through 16, or postnatal days (PND) 3 through 5. In the postnatal exposure period rat pups were injected (s.c.) with three consecutive daily doses of 0, 5, 10, or 20 mg/kg RA on PND 3 through 5. This postnatal exposure had no detectable effect on survival, body or brain weight. In contrast, there was a marked sensitivity to RA in the GD 11-13 group. Many pups from dams given 10 mg/kg RA PO on GD 11-13 were found dead in the cage on the day of birth, and all surviving pups died within 4 days of birth. Examination of milkbands revealed no evidence of effective suckling in these short-term survivors. The same 10 mg/kg dose at GD 8-10 or GD 14-16 produced much lower mortality and pups appeared to suckle normally. To produce adequate PND 28 survival in the GD 11-13 group, it was necessary to reduce dosage to 2.5 mg/kg daily. Even this lower exposure produced effects on PND 28 body and brain weight, significantly lowering weights of body (84% of control), whole brain (94%), and cerebellum (90%). Cerebellar weight was also depressed as percent of whole brain weight, suggesting an effect focused specifically on this region. RA at 10 or 12.5 mg/kg over GD 14-16 also reduced cerebellar weight (92% and 91% of control, respectively). Thus, exposure on GD 14-16 had effects similar to those seen at GD 11-13, but only at considerably higher doses. In contrast, exposure to RA on GD 8-10 did not affect whole body or brain weight, and of eight brain regions examined, only brain stem weight was reduced (91% of control). The GD 8-10 exposure also differed substantially from later exposures in that it was the only treatment to produce substantial malformations, including exencephaly, eye and skeletal defects. We conclude that gestational exposure to RA produces lethality and regional brain stunting that is dose and developmental stage specific, with a pronounced sensitive period on GD 11-13. In contrast, the GD 8-10 period is most sensitive for production of malformations, albeit at somewhat higher doses.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

A behavioral and neuroanatomical investigation of the lethality caused by gestational day 11-13 retinoic acid exposure.

In a companion article, we report that there is a sensitive period for all-trans retinoic acid (RA) lethality on gestational days (GD) 11-13. When dams were given 10 mg/kg RA daily for 3 consecutive days on GD 11-13, a number of pups were found dead in the home cage on the day of birth, and the remainder inevitably died due to an apparent inability to nurse. Here we report a set of experiments further investigating these effects. Dams were exposed PO to 10 mg/kg RA or oil vehicle on GD 11-13. Fetuses were removed by Cesarean section on the afternoon of GD 21, culled, and fostered to non-treated dams that had given normal vaginal delivery a day earlier. Maternal behavior was observed for the first 6 h after fostering. The next morning all surviving pups were given a brief behavioral evaluation, including the ability to attach to the nipple of anesthetized foster dams. At the time of C-section, culls were killed and brains were quickly removed and placed in fixative. A series of paraffin-embedded, cresyl-violet-stained serial sections of a representative brain stem from each litter was prepared. RA exposure did not increase fetal mortality. Treated litters were as large as controls, and virtually all treated fetuses were alive in utero. However, unlike controls, some treated fetuses appeared to have difficulty in initiating spontaneous breathing when delivered by C-section, and considerable physical stimulation was required before normal breathing began. As in the previous report, RA-exposed pups did not have milk in their stomachs after 18 h on the foster dam; further, they did not attach to the maternal nipple, and they had greater difficulty than controls in maintaining an upright posture. Examination of serial sections of the medulla indicated that the hypoglossal nucleus appeared grossly normal in the RA-exposed pups. In contrast, the inferior olive and the area postrema were affected by RA exposure. Both nuclei were normally located, but exhibited reduced cell density and/or intensity of staining. In the inferior olive the dorsal and principal nuclei were primarily affected, to the degree that about one quarter of treated brains had no identifiable principal nucleus. We conclude that RA exposure on GD 11-13 causes abnormal development of cell-dense regions of the medial medulla, and these abnormalities may account for the difficulty these animals experience in beginning spontaneous breathing and in nursing. These breathing and nursing problems in turn almost certainly account for the high mortality seen during natural birth and for the subsequent failure to thrive, respectively.

Animals↗

PubMedDate not supplied

Behavioral effects of low-dose gestational day 11-13 retinoic acid exposure.

In a comparison article we report that maternal PO exposure to 2.5 mg/kg all-trans retinoic acid (RA) daily for 3 consecutive days over gestational days (GD) 11-13 produces a 10% reduction in weight of cerebellum at 4 weeks of age, not accompanied by other malformations. Here we report the results of a preliminary behavioral analysis of offspring exposed gestationally to RA as above. Exposed dams were allowed to deliver normally, and litters were culled to eight pups (4 +/- 1 of each sex) at birth. Both male and female offspring were tested prior to weaning on GD 21. Thereafter females were killed on postnatal day (PND) 28 for verification of RA effects on regional brain weight, and all subsequent behavioral testing was conducted on males. Preweaning tests were restricted to negative geotaxis (PND 8-9) and open field activity (PND 22). Postweaning tests included open field activity (PND 43), auditory startle response (three times, on PNDs 22, 43, and 84), 2-week activity in residential running wheels (PNDs 62-76), complex maze performance for 5 consecutive days (PND 83-87), emergence latency (PND 106), and assessment of the behavioral response to an amphetamine challenge (PND 107). Males were then killed on PND 108 for verification of RA effects on regional brain weights. In this study, RA reduced weight of cerebellum but not striatum. Cerebellar weight was 92% of control values in PND 28 females, and this weight difference had diminished to 95% of control weight by PND 108 in males. There were no treatment effects on negative geotaxis, activity in a small open field, auditory startle amplitude, or latency to enter an illuminated alley from a dark chamber. Maze learning occurred at levels equal to or slightly better than controls. Running wheel activity was enhanced by RA exposure, whereas activity in response to an amphetamine challenge was reduced by such exposure. We conclude that RA doses low enough to produce mild weight reductions in cerebellum, without attendant malformations, can alter behavior. The precise nature of these alterations remains to be elucidated, but the findings reported here suggest that effects may be more pronounced on activity than on learning.

Animals↗

PubMedDate not supplied

Minimal behavioral effects from moderate postnatal lead treatment in rats.

Developmental lead exposure continues to be a worldwide problem. This study investigated the behavioral effects resulting from developmental lead treatment in rats with corresponding physiological measures of lead exposure. Sprague-Dawley rats were treated with 350 ppm lead acetate from birth to weaning via the dam's drinking water. Behavioral measures assessed in the offspring included residential activity tests, complex maze performance, acoustic startle response, emergence behavior (light/dark preference), prepulse inhibition, and ethological assessments of play, dominance, and burrowing. Pb blood levels averaged 53 microg/dl in the dam at the time of offspring weaning and 46 microg/dl in weanling female offspring. Pb levels averaged 277 ng/g and 32 microg/g in the brain and bone, respectively, of female offspring at weaning. No behavioral assessment indicated any lead-related functional alterations nor were there any statistically significant differences when the lead-treated group was restricted to rats in those litters that were above the median Pb blood lead level at weaning. These results indicate that any lead-related functional alterations at this dose may be subtle and require a sufficient demand on the system for detection.

Animals↗

PubMedDate not supplied

Neonatal dexamethasone on day 7 causes mild hyperactivity and cerebellar stunting.

To investigate the effects of glucocorticoid treatment on central nervous system development, rats were injected with dexamethasone (DEX) (1-3 mg/kg) on postnatal day (PND) 3 or 7. DNA and protein content and concentration were measured in the cerebellum and hippocampus on PND 28 and 112. Whole and regional brain weights were measured at PND 28, 84, and 112. Nest odor preference (PND 10-11), open field activity (PND 18-21), running wheel activity (PND 50-56), and complex maze performance (PND 60-63) were measured in rats treated twice with 1.5 mg/kg DEX on PND 7. DEX treatment on PND 7 resulted in reductions in PND 28 whole brain and regional weights (frontal cortex, cerebellum, and brain stem) and, by PND 112, all except whole brain and cerebellar weights had recovered. A mild syndrome of hyperactivity (increased open field rearing and activity) was apparent in rats treated with DEX on PND 7. These results are discussed in terms of the developmental stage specificity in production of brain, and, specifically, cerebellar insults and their resulting effects.

Animals↗

PubMedDate not supplied

Gestational stage-specific effects of retinoic acid exposure in the rat.

Although, or perhaps because, retinoids are among the earliest known behavioral teratogens, there is still little agreement about the behavioral effects of stage-specific exposure to these compounds. In these studies, pregnant albino rats were gavaged once daily with retinoic acid (RA) for 3 consecutive gestational days (GD), GD 8-10), GD 11-13, or GD 14-16. Dose levels were maximal levels compatible with survival (10, 2.5, or 12.5 mg/kg RA, over GD 8-10, 11-13, and 14-16, respectively). Two studies were conducted. The first assessed the effects of RA exposure on GD 8-10 or 14-16 on regional brain weight and on a large behavioral test battery. The second study assessed the effects of RA exposure on GD 11-13 or GD 14-16 on many of the same variables. Taken together with an earlier study of the behavioral effects of GD 11-13 RA exposure, these studies permit the following conclusions. 1) RA exposure at the above doses at any of the three exposure periods produced an apparent reduction in amphetamine-induced open field activity. 2) RA exposure on GD 14-16 but not earlier produced a robust, replicable rotarod deficit in exposed offspring. 3) RA exposure on GD 11-13, but not earlier or later, increased daytime activity in residential running wheels. 4) RA exposure on GD 11-13 or GD 14-16 but not GD 8-10 reduced weight of cerebellum. 5) No RA effect at any exposure period was seen on maze learning, activity in novel open fields, or on auditory startle.

Amphetamine↗

PubMedDate not supplied

The effect of teratogens on maternal corticosterone levels and cleft incidence in A/J mice.

It is unknown whether orofacial clefting, one consequence of teratogenic exposure, results from a direct interaction between the teratogen and the embryonic palate, or indirectly from maternal alterations caused by the teratogen. In the current study pregnant A/J mice were exposed to one of three cleft-inducing agents in order to examine the relationship between drug-induced clefting and the response of maternal plasma corticosterone to drug administration. The agents used, haloperidol (HAL), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), or phenytoin (PHT), were administered in teratogenic doses between 0800 and 0930 on gestational day 10 (GD 10). For corticosterone determinations, mice were dosed on GD 10, and blood was collected at 1, 4, 24, or 48 hr after dosing. For fetal evaluation of cleft lip and/or cleft palate, mice were dosed on GD 10 and killed on GD 18. Phenytoin was the most potent inducer of cleft lip and palate and induced a sustained elevation of plasma corticosterone in maternal animals. The other treatments, in order of decreasing potency to induce clefting and/or cause an elevation of corticosterone in plasma were 2,4,5-T > HAL > controls. Correlations between maternal corticosterone levels and clefting incidence were very high at all time points examined; total exposure (area under the curve) was also highly correlated. A linear relationship between drug-induced increases in maternal corticosterone levels and the incidence of clefting in A/J mice was evident. Based on these findings, we believe that increased maternal corticosterone levels may play a role in orofacial clefting in A/J mice.

2,4,5-Trichlorophenoxyacetic Acid↗