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R R Holson

Publications and source records attributed to R R Holson.

At least 37 records · Page 2Linked to original sources
PubMed1993

Behavioral effects of methylazoxymethanol-induced micrencephaly.

This study was prompted by reports of functionally normal humans with micrencephaly or cortical hypoplasia. Methylazoxymethanol acetate (MAM) treatment, which induces micrencephaly in rats, was administered by injection (20 mg/kg) on gestational day 14. Prior to weaning and into adulthood, offspring were assessed on many behavioral tests. There were 3 findings. First, MAM rats (forebrain weight less than 2/3 of controls) were not profoundly hyperactive. Increased activity was seen only on prolonged tests or after amphetamine administration. Second, MAM rats were hypoactive in some conditions. These rats were light shy and less likely to explore lighted areas. MAM rats appeared hyperreactive to environmental stimuli, but not hyperactive. Finally, no MAM effect on behavior was as large as that on brain weight. Thus, as with clinical findings, rat micrencephalics are more remarkable for functional sparing than for behavioral abnormalities.

Alkylating Agents↗
PubMed1993

Haloperidol effects on the developing dopamine system: conflicting results and implications for neurobehavioral teratology research.

In an attempt to further develop basic principles to guide research in neurobehavioral teratology, six experiments were conducted to examine the effects of prenatal haloperidol (a D2 dopamine antagonist) exposure on striatal D1 and D2 binding sites. Another laboratory has repeatedly reported that prenatal exposure to this dopamine antagonist reduces striatal dopamine binding sites in exposed offspring. Our initial studies were successful in replicating and extending these previously reported reductions in D2 dopamine binding sites in caudate of rats exposed prenatally to haloperidol. However, additional experiments in our laboratory, in which pups were exposed to a range of haloperidol doses over gestational periods when the dopamine system has been reported to be most vulnerable to prenatal haloperidol exposure effects, have repeatedly failed to replicate our initial findings. Three other laboratories have also failed to duplicate this effect. The results of these studies suggest that beyond "standard" confounding variables, neurobehavioral teratologists are faced with as yet poorly understood factors that influence replication of findings within and between laboratories. These findings also emphasize the importance of within- and between-laboratory replication of experimental findings.

Animals↗
PubMed1992

Prenatal dexamethasone exposure in rats: effects of dose, age at exposure, and drug-induced hypophagia on malformations and fetal organ weights.

Glucocorticoids cause stunting and cleft palate in rodents. The aim of this study is to identify fetal organs and developmental periods sensitive to stunting induced by maternal exposure to dexamethasone (DEX). DEX (0.2 or 0.4 mg/kg) or saline was given sc to pregnant CD albino rats on Gestation Days (GD) 9-14 or 14-19. On GD 20 dams were euthanized. Fetuses were weighed and examined for cleft palate. Eight fetuses/litter were randomly selected, and weights were obtained. Fetal skeletons were examined for abnormalities, and long bone measurements were taken. A dose-related decrease in maternal and fetal body weights occurred at both exposure periods. Developmental stage-specific malformations were noted in the high-dose group on GD 9-14 (cleft palate) and on GD 14-19 (wavy ribs). A dose-response in stunting occurred in all organs except cerebellum in at least one exposure period. Across both exposure periods the brain, heart, testes, and long bones were relatively resistant to DEX. Sensitive organs included thymus, spleen, adrenals, lungs, liver, and kidneys. DEX substantially reduced maternal food intake and increased water intake in some dams. Pair-feeding experiments suggested that the hypophagic effect of DEX was not responsible for the noted malformations and had little impact on growth stunting. The present findings have identified fetal organs, skeletal regions, and developmental periods sensitive to DEX exposure.

Abnormalities, Drug-Induced↗
PubMed1992

Embryotoxicity of phenytoin in adrenalectomized CD-1 mice.

It has been proposed that the anticonvulsant drug phenytoin (PHT) and glucocorticoids induce orofacial clefting by the same mechanism. Previous work had demonstrated that PHT treatment significantly increased endogenous maternal corticosterone concentrations for approximately 48 hr after dosing in A/J mice. The purpose of the present investigation was to determine whether PHT is embryotoxic in the absence of endogenous maternal glucocorticoids. Maternal adrenal glands were removed on Day 7 of gestation, and the incidence of clefting after PHT treatment was determined. There was a high level of maternal toxicity following adrenalectomy (ADX) and PHT treatment at either 60 or 75 mg/kg. This increased toxicity did not appear to be due to altered maternal drug levels in ADX mice. There was a significant increase in the clefting incidence among offspring of ADX dams treated with PHT at 60 mg/kg. This dose of PHT did not elevate maternal corticosterone levels in ADX dams. These data suggest that PHT is capable of producing clefts in the absence of endogenous maternal corticosterone.

Abnormalities, Drug-Induced↗
PubMed1992

The influence of environmental temperature on the transient effects of methamphetamine on dopamine levels and dopamine release in rat striatum.

When male rats were injected four times (once every 2 hr) with 5 mg/kg methamphetamine (METH) at an environmental temperature of 23 degrees C, transient changes occurred in the levels of striatal dopamine (DA) and the regulation of striatal DA release. Striatal DA levels were minimally affected 1 day after METH treatment, but 3 days after METH treatment, striatal DA levels decreased to approximately 40% of control. DA levels returned to 70% of control 2 weeks after METH. Similarly, striatal tyrosine hydroxylase (TH) activity decreased to approximately 50% of control activity 3 days after METH treatment at 23 degrees C, but did not differ from controls at 1 or 14 days after METH treatment. No changes in striatal DA levels were observed in rats treated with four doses of 5 mg/kg METH at an environmental temperature of 4 degrees C. Striatal DA levels decreased modestly to approximately 70% of controls 3 days after treatment with four doses of 10 mg/kg METH at 4 degrees C, but DA levels returned to control levels 14 days after METH treatment. Furthermore, striatal TH activity was not affected by 10 mg/kg METH at 4 degrees C. Thus, a cold environmental temperature (4 degrees C) reduced the effects of METH on striatal DA levels and striatal TH activity. Changes in the presynaptic regulation of DA release after either 5 mg/kg (23 degrees C) or 10 mg/kg (4 degrees C) METH treatment were determined in vitro using striatal slices.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

"Isolation stress" revisited: isolation-rearing effects depend on animal care methods.

Early reports of enhanced behavioral reactivity in isolation-reared rats attributed this syndrome to "isolation stress." In the studies reported here, this "isolation stress syndrome" was reliably obtained in adult rats reared from weaning in individual hanging metal cages. Such isolates showed behavioral and adrenocortical symptoms of profound fear during open-field testing, unlike group-housed controls or littermate isolates reared singly in plastic cages. Animals in hanging metal cages are never touched by human caretakers, whereas rats reared in plastic cages are picked up and put in clean cages twice weekly. Handling hanging-cage isolates twice weekly to model the handling associated with cage changes completely protected against this syndrome. Further, there was no hormonal, neurochemical or anatomical evidence of chronic stress even in hanging-cage isolates. Littermates housed in social groupings (three rats per plastic cage) also froze and defecated in the open field at rates comparable to hanging-cage isolates if they were the first animals to be tested from their social group cage. It is probable that odor cues from familiar cagemates in the open field protected socially reared animals tested subsequently from the same cage from this syndrome. It is concluded that isolates are not chronically stressed, and that rearing effects are the result of a complex interaction between prior handling, social experience and test conditions.

Animals↗
PubMed1991

Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in rat caudate.

Extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and serotonin (5-HT) were assayed in the caudate of freely moving rats using microdialysis and high performance liquid chromatography with electrochemical detection (HPLC-EC) to detect changes in their release. Dialysates were assayed at 20-minute intervals for four hours after an intraperitoneal (IP) injection of MDMA (10 mg/kg). In a separate study to determine MDMA effects on total caudate levels of the above neurochemicals, animals were injected IP with MDMA (10 mg/kg) and then sacrificed at 20, 60, 120 and 180 minutes after treatment. Brains were quickly removed, and caudate nuclei were dissected for neurochemical analysis using HPLC-EC. MDMA elicited an amphetamine-like increase in DA release, followed by an increase in DA content. DOPAC and HVA were both reduced in homogenate. 5-HT release was also increased, followed by a drop in caudate homogenate levels by three hours. DA extracellular content was 686% of control at 80 minutes; caudate homogenate levels were 122% at 120 minutes. 5-HT extracellular release was 123% at 20 minutes, then decreased thereafter. It is concluded that the acute effect of MDMA on caudate is at least as great on the DA as it is on the 5-HT system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Interactions of MK-801 with glutamate-, glutamine- and methamphetamine-evoked release of [3H]dopamine from striatal slices.

The interactions of MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine], glutamate and glutamine with methamphetamine (METH)-evoked release of [3H]dopamine were assessed in vitro to determine whether MK-801 inhibition of METH neurotoxicity might be mediated presynaptically, and to evaluate the effects of glutamatergic stimulation on METH-evoked dopamine release. MK-801 inhibition of glutamate- or METH-evoked dopamine release might reduce synaptic dopamine levels during METH exposure and decrease the formation of 6-hydroxydopamine or other related neurotoxins. Without Mg++ present, 40 microM and 1 mM glutamate evoked a N-methyl-D-aspartate receptor-mediated [3H]dopamine and [3H]metabolite (tritium) release of 3 to 6 and 12 to 16% of total tritium stores, respectively, from striatal slices. With 1.50 mM Mg++ present, 10 mM glutamate alone or in combination with the dopamine uptake blocker nomifensine released only 2.1 or 4.2%, respectively, of total tritium stores, and release was only partially dependent on N-methyl-D-aspartate-type glutamate receptors. With or without 1.50 mM Mg++ present, 0.5 or 5 microM METH evoked a substantial release of tritium (5-8 or 12-21% of total stores, respectively). METH-evoked dopamine release was not affected by 5 microM MK-801 but METH-evoked release was additive with glutamate-evoked release. Without Mg++ present, 1 mM glutamine increased glutamate release and induced the release of [3H]dopamine and metabolites. Both 0.5 and 5 microM METH also increased tritium release with 1 mM glutamine present. When striatal slices were exposed to 5 microM METH this glutamine-evoked release of glutamate was increased more than 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Ontogeny of the enhanced behavioral response to amphetamine in amphetamine-pretreated rats.

Repeated administration of amphetamine to adult rats results in enhanced behavioral responses to subsequent amphetamine exposure. These experiments were designed to determine the earliest age at which behavioral sensitization to amphetamine could be detected. Rats from both sexes (n = 6-8/group) at ages of 1, 7, 21 or 49 postnatal days (PNDs) were injected with either d-amphetamine sulfate (5 mg/kg) or saline, SC, twice daily for 5 consecutive days. Stereotyped behavior and locomotor activity responses to a challenge dose of d-amphetamine (2.5 mg/kg), or saline, IP, were assessed for a total of 90 min, 15 days after the last dose of pretreatment. Amphetamine-induced stereotyped behavior was significantly enhanced only when amphetamine pretreatment was initiated at PND 49, but not at the earlier ages of PND 1, 7 or 21. There was no apparent sex difference in this effect. Correspondingly, amphetamine-induced locomotor activity was reduced in both sexes of the same age group (PND 49), but not in groups pretreated earlier, when compared to the saline-pretreated rats. These results suggest that amphetamine sensitization may be a late-developing effect, one which occurs sometime after the 3rd week of postnatal life.

Aging↗
PubMed1989

Neurochemical effects of prenatal haloperidol exposure.

The neurochemical effects of prenatal exposure to dopamine receptor antagonists are as yet poorly characterized. To further examine this problem, pregnant rats were given daily subcutaneous injections of vehicle, 2.5 or 5.0 mg/kg haloperidol over gestational days 6 through 20. Membrane binding of [3H]SCH-23390 (D1-specific) and [3H]spiroperidol (D2-specific in most brain areas) was measured in four regions of the cerebral dopamine system at postnatal day (PND) 30. Dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured in caudate on PND 30 following a d-amphetamine challenge. Prenatal haloperidol exposure reduced [3H]SCH-23390 and [3H]spiroperidol binding in caudate in a dose-dependent manner. [3H]Spiroperidol binding was similarly reduced in nucleus accumbens, but only the low dose (2.5 mg/kg) group showed decreased [3H]SCH-23390 binding in this region. Binding of neither compound was significantly altered in amygdala or frontal cortex. Basal or drug-stimulated levels of caudate DA and DOPAC were unaltered. It is concluded that prenatal haloperidol exposure reduces D1 and D2 binding in some, but not all regions of the forebrain dopamine system.

Amphetamine↗
PubMed1989

Behavioral effects of prenatal haloperidol exposure.

Pregnant albino rats were exposed to vehicle (CON), 2.5 mg/kg (LOW) or 5.0 mg/kg (HIGH) haloperidol (HAL) from the sixth through the twentieth day of gestation. The effect of prenatal HAL exposure on offspring was assessed with the following five behavioral measures: 1) milk-induced behavioral activation on the sixth postnatal day (PND 6), 2) shock-precipitated wall climbing (PNDs 9, 11, 13, 15 and 17), 3) amphetamine-induced stereotypies (PND 30), 4) apomorphine-induced stereotypies (PND 30) and 5) duration of barbiturate anesthesia (PNDs 34 and 62). Measures taken very early in life indicated that prenatal HAL reduced arousal. Inactivity scores were elevated in HAL-exposed pups on PND 6 during milk-induced behavioral activation. Shock-precipitated wall climbing was reduced in the HAL animals on PNDs 9 and 11, but not thereafter. At PND 30, no prenatal treatment effect was detectable on stimulant-induced stereotypies or on duration of barbiturate anesthesia. On PND 62, barbiturate anesthesia duration was significantly reduced in both sexes of HIGH HAL animals. These findings suggest that prenatal HAL effects follow a dynamic, changing course as the exposed rat pup matures. Early reductions in arousal (milk-induced behavior and shock-precipitated wall climbing) wane with age, perhaps to be replaced by an actual increase in arousal as HAL pups approach adulthood.

Anesthesia↗
PubMed1989

Chronic prenatal haloperidol exposure: lack of effect on presynaptic dopamine autoreceptors.

Prenatal haloperidol exposure in rats is known to reduce striatal D2 receptor binding in postnatal day (PND) 30 offspring. The effects of prenatal haloperidol exposure on presynaptic dopamine (DA) autoreceptor function are not well described. Pregnant albino rats were given daily injections of haloperidol (2.5 or 5.0 mg/kg, sc) or vehicle over gestational days 6-20. Presynaptic DA autoreceptor function was assessed using the DOPA decarboxylase inhibitor NSD-1015 and gamma-butyrolactone in the caudate, nucleus accumbens and olfactory tubercles of male offspring sacrificed on PND 97. There appeared to be no impairment of autoreceptor function in any region studied. The data indicate that prenatal haloperidol exposure does not result in permanent alterations in presynaptic DA autoreceptor function.

4-Butyrolactone↗
PubMed1989

Behavioral and neurochemical effects of orally administered MDMA in the rodent and nonhuman primate.

MDMA (methylenedioxymethamphetamine) is a recreational drug of abuse known as "Ecstasy" which markedly decreases regional brain serotonin (5-HT) content and produces 5-HT nerve terminal degeneration in forebrain areas of the rat. In order to determine the acute and chronic behavioral effects of MDMA, adult rats were given MDMA at 0, 5 or 10 mg/kg, po for 4 consecutive days. Alternatively, parachloroamphetamine (PCA) at 5 mg/kg was administered under the same regimen. Within 30 min after the first dose, the MDMA-treated rats exhibited the serotonin motor syndrome consisting of straub tail and splayed hindlimbs comparable to that seen in the PCA-treated rats. This serotonin motor syndrome, with a duration of about 2 hr, was less pronounced after subsequent doses. At 2-4 wk after the last dose, no significant differences between control and treated rats were seen in emergence, hot plate response, auditory startle response or complex maze behavior even though a significant dose-related decrease (50%) in 5-HT concentration was observed in the frontal cortex and hippocampus of these rats 4 wks after the last dose. Adult female monkeys dosed po with 5 or 10 mg/kg of MDMA twice/day for 4 consecutive days demonstrated no spontaneous behavioral changes or weight loss compared to controls, but forebrain 5-HT concentration was reduced by 80% 1 mon after dosing. These data indicate that at doses only 2-3 times the human dose, MDMA produces significant forebrain 5-HT decreases but does not produce detectable residual behavioral alterations as assessed by these behavioral paradigms.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Benzodiazepine-like behavioral effects following withdrawal from chronic delta-9-tetrahydrocannabinol administration in rats.

Chronic exposure to cannabis extract or delta-9-tetrahydrocannabinol (THC) has been reported to produce hippocampal neuropathology in rats, as well as classical "hippocampal" behavioral deficits. In an attempt to replicate and extend these findings, male rats were exposed to THC for 13 consecutive weeks, beginning in early adolescence. Drugs were administered five consecutive days a week (Monday through Friday). There were five dose levels: vehicle control, 5, 10, or 20 mg/kg, p.o., and 20 mg/kg THC four days a week (Monday-Thursday), followed by 60 mg/kg on Friday. Following THC exposure, all animals were withdrawn from drugs for seven weeks prior to behavioral testing. Three behavioral tasks previously shown to be sensitive to hippocampal damage were assessed. These were habituation of open-field activity, 24-hr passive avoidance response retention, and complex maze performance. A fourth task, emergence latency, was also included because it has been determined to be sensitive to "anxiety" levels. To facilitate interpretation of the complex maze data, two additional experiments are also reported. One experiment tested rats exposed to trimethyltin (TMT, a potent hippocampal neurotoxicant) on the complex maze. The second assessed the affects of chronic/acute benzodiazepine (BZ) exposure upon maze performance. Test results did not suggest that chronic THC exposure produced behavioral deficits resembling those seen following hippocampal damage. Habituation rates in an activity monitor were identical for all exposure groups, and there was no passive avoidance retention deficit. Further, while TMT caused pronounced abnormalities in the complex maze, chronic THC exposure at the two highest dose levels significantly improved maze performance, similar to BZ effects on this task. Chronic THC also appeared to reduce freezing on the emergence task, another anxiolytic-like effect. These results support other reports of persistent long-term behavioral effects of chronic THC exposure. However, they suggest that some behavioral effects may more closely resemble the effects of minor tranquilizers rather than hippocampal damage.

Animals↗
PubMed1988

Adrenocortical, beta-endorphin and behavioral responses to graded stressors in differentially reared rats.

Isolation rearing has long been suspected to alter hormonal and behavioral responses to stress. Two experiments were conducted to test the hypothesis that isolates are more timid or fearful than socially reared rats when exposed to novel test environments. In both, isolate response to 3 graded stressors was compared to that of socially-reared rats. In the first experiment, animals were handled, shocked or not treated prior to testing to produce three levels of conditioned fear. They were then tested on four paradigms previously shown sensitive to conditioned fear: open field activity, emergence latency, auditory startle, and latency to accept food from the experimenter. In the second experiment, rats were given a 0-, 5- or 20-min forced swim, then sacrificed for analysis of plasma corticosterone and pituitary and hypothalamic beta-endorphin. It was found that isolates showed little evidence of enhanced behavioral timidity, although rearing effects were seen on all 4 behavioral measures. Plasma corticosterone levels increased in a graded fashion over the course of the forced swim, but there was no effect of rearing conditions. While there were no effects of rearing or stress on hypothalamic beta-endorphin, pituitary beta-endorphin content was lower in females than in males, and isolate males had lower pituitary endorphin than social males. In summary, these experiments provide no evidence that isolation rearing produces a primary, global increase in fearfulness, but identify several behavioral and hormonal differences associated with differential housing in rats.

Animals↗
PubMed1988

Alterations in maternal plasma corticosterone levels following treatment with phenytoin.

The mechanisms of the embryotoxic effects of the anticonvulsant drug, phenytoin (PHT), are unknown. Glucocorticoids and PHT demonstrate similar embryopathic effects and strain sensitivity in that A/J mice are very sensitive to the embryopathic effects of synthetic glucocorticoids and PHT while C57BL/6 (B6) mice are comparatively resistant to both. It is possible that teratogenic consequences of PHT are not a result of drug interaction at the target site but are mediated indirectly by glucocorticoids. In this study, PHT was administered by intraperitoneal injection at 25 (a nonteratogenic dose) or 75 mg/kg body weight (a teratogenic dose) to pregnant A/J mice on Day 10 of gestation. Mice of the B6 strain received the drug at 75 mg/kg on Day 10. Control mice received vehicle (pH 11.0 distilled water). Dams were killed at various times after the injection; plasma samples were obtained, and corticosterone levels were determined by radioimmunoassay. In control animals, maternal plasma corticosterone levels were elevated soon after dosing but gradually declined, except for an apparent circadian rhythm effect seen in samples obtained in the afternoon. Administration of a nonteratogenic dose of PHT to A/J mice caused a temporary increase in plasma corticosterone levels which decreased to the control level between 6 and 24 hr following dosing. Treatment with a teratogenic dose in A/J mice led to plasma levels that remained elevated for the entire 48-hr period examined in this study. In B6 mice, treatment with 75 mg/kg increased plasma corticosterone levels for 24 hr, after which they declined to the control value by 30 hr. The adrenal corticosteroid response of A/J mice to PHT appeared to be much more sensitive than that of B6 mice, and there appeared to be a relationship between plasma levels of PHT and corticosterone. The lengthy increase in plasma corticosterone during organogenesis may be a factor in the increased incidence of cleft lip and palate seen after administration of PHT to A/J mice.

Animals↗
PubMed1988

Neuropathological evaluation by combined immunohistochemistry and degeneration-specific methods: application to methylenedioxymethamphetamine.

To best interpret the significance of neurological alterations produced by chemicals, the changes in morphological as well as neurochemical parameters must be measured and compared to each other. We have devised an approach to readily label microscopic sections for multiple antigens (neurotransmitters, enzymes, peptides, etc.) as well as for the demonstration of degenerating structures by silver impregnation. Here, we applied silver-staining together with immunolabelling of 5-HT and tyrosine hydroxylase (the rate-limiting enzyme for dopamine synthesis) to study neurohistological alterations produced by methylenedioxymethamphetamine (MDMA), a hallucinogenic stimulant previously used as an adjunct to psychotherapy and now a popular recreational drug ("Ecstasy"). Single oral doses of 40 or 80 mg/kg MDMA doubled the density of silver-impregnated (degenerating) fiber terminals in the caudate nucleus compared to controls, when rats were sacrificed 18 hours after treatment. Four months after two 40 mg/kg oral doses per day for four days, rats had a reduced neurochemical content of 5-HT in the hippocampus, and fewer immunostainable 5-HT axons per unit area in the hippocampal stratum lacunosum but no change in brain-stem neurochemical 5-HT content or in the numeric density of 5-HT-positive cell bodies in the dorsal raphe nucleus. The neurohistology suggests interpreting the changes in neurochemical content of serotonin produced by MDMA as due to degeneration followed by subsequent loss of 5-HT axons, rather than a decrease in the rate of neuronal 5-HT synthesis or a toxicity directed toward 5-HT cell bodies. The combination of neurohistological and neurochemical evaluation will continue to prove useful in comprehensive evaluation of the neurological effects of chemical exposure.

3,4-Methylenedioxyamphetamine↗