Biomedical subjects

R R Holson

Publications and source records attributed to R R Holson.

At least 55 records · Page 3Linked to original sources

PubMed1988

Neurochemical evaluation of rats prenatally exposed to the adrenergic agonists clonidine and lofexidine.

Clonidine (CLON), an alpha-2 adrenergic agonist, is widely used to reduce hypertension; it is also recommended for blocking acute opiate withdrawal. Lofexidine (LOF), a CLON analog, is an investigational compound being readied for the marketplace. Since exposure to both drugs is likely to occur in the last two trimesters of human pregnancy, it is important to determine whether such exposure can have effects upon brain or behavior of offspring. Pregnant CD rat dams were given daily subcutaneous injections of saline, CLON, or LOF on days 8 through 20 of gestation. Maternal weight during gestation, neonatal weight and neurochemical measures were monitored. Maternal body weight was reduced in a dose dependent manner. At PND 1 brain ornithine decarboxylase (ODC) activity was reduced in LOF- but not CLON-exposed pups of both sexes. At this age no alteration was seen in whole brain catecholamine levels or in whole brain alpha-2-adrenergic binding.

Adrenergic alpha-Agonists↗

PubMed1988

Behavioral evaluation of rats prenatally exposed to the adrenergic agonists clonidine and lofexidine.

Clonidine (CLON), is a widely used antihypertensive agent with a potential for expanded therapeutic application in combating drug withdrawal symptoms in opiate and alcohol addiction. Recently, CLON and an analogue lofexidine (LOF) have been shown to block the opiate withdrawal syndrome in a variety of species, including man. One new application of these agents may be as an alternative to methadone maintenance for pregnant opiate addicts. Any consideration along these lines will require screening for reproductive outcome and behavioral teratogenic effects. Dams were given s.c. injections of CLON (0.16 or 0.64 mg/kg) of LOF (0.64 or 2.56 mg/kg) once daily from gestational day (GD) 8-20. Neonatal body weights, at postnatal days (PNDs) 2, 15 and 30 were reduced in a dose-dependent manner, with LOF-induced reduction twice that of CLON. No significant differences were obtained on negative geotaxis, an auditory startle test, or a series of swimming immobilization tests across the periadolescent period. A series of activity measures carried out on PND 12, 14, 16 and 18 showed minor differences in the high dose LOF male animals, but not in any of the other drug-treated groups.

Animals↗

PubMed1986

Feeding neophobia: a possible explanation for the differential maze performance of rats reared in enriched or isolated environments.

This study undertook a detailed examination of the now-classical isolate maze deficit. Three male littermates from each of 19 litters were exposed to early and lengthy environmental enrichment, isolation, or isolation plus frequent handling. At 120 days of age subjects were tested on the open field, on an emergence task, and in a complex maze. Subjects were allowed to enter and leave the maze goal box at will. Only after eating for 30 seconds were they captured and replaced in the start box for the next trial. In the open field and emergence tasks the enriched and isolate rats both showed symptoms of much greater timidity than the experimenter-adapted handled rats. In the maze, enriched rats increased goal box entries over days, handled and non-handled isolates did not. By day three, handled and non-handled isolate goal entries were significantly lower than for enriched rats. This finding suggests an intellectual deficit in isolate maze learning. However, error analysis revealed that even on day one, all groups made errors at a rate far below random. The pattern of errors implied that subjects were often actively avoiding the goal, with isolates turning aside before entering the goal significantly more often than enriched rats. These findings suggest that the isolate maze deficit is due to a form of feeding neophobia. More generally, it would appear that these behavioral differences reflect early learning, with handled rats less afraid of humans and enriched rats better adapted to eating in novel surroundings.

Animals↗

PubMed1986

Mesial prefrontal cortical lesions and timidity in rats. I. Reactivity to aversive stimuli.

Two experiments were conducted to assess the degree to which mesial prefrontal cortical (MFC) lesions in male rats alter the behavioral manifestations of fear (timidity). The first experiment gauged the reactivity to the threat of electroshock. MFC lesions did not alter the incidence of freezing in a box associated with shock. MFC and sham-lesioned subjects made few errors when they were required to run from an open field into a small compartment to avoid shock, but displayed the classical MFC deficit when forced to run in the opposite direction. MFC lesions also increased the latency to enter an open field when the field was novel or aversive, but not when it was familiar. In a second experiment, it was found that the classical MFC hoarding deficit occurred when rats had to traverse an illuminated but not a dark runway to reach food pellets. Similarly, burrowing was normal when subjects had to burrow to escape from an open field, but not when they had to enter an open field to burrow. It is concluded that damage restricted to MFC enhances timidity, and that this effect accounts for several behavioral alterations that contribute to the MFC lesion syndrome.

Animals↗

PubMed1986

Mesial prefrontal cortical lesions and timidity in rats. II. Reactivity to novel stimuli.

An earlier set of experiments suggested that mesial prefrontal cortical (MFC) lesions in rats enhanced timidity. It was uncertain whether this increased timidity was a general phenomenon, or was restricted to fear of bright, open spaces. The experiments reported here measured behavioral reactivity to a variety of stimuli, under situations where light/dark differences were minimized. It was found that MFC rats were slowed in leaving an open field to enter a small box. In the open field, MFC subjects showed signs of enhanced reactivity, but only when the field was novel and the subjects unhandled. When allowed to choose between four alleys containing varying stimuli, brain-damaged rats avoided novel objects and complex stimuli, but spent more time than controls in contact with other rats in the apparatus. In a test of food neophobia, MFC subjects were not neophobic in a familiar test environment, but did avoid the experimenter more than controls. Finally, duration of barbiturate anesthesia was shortened by MFC lesions, but only under conditions of high novelty. It is concluded that MFC lesions produce a timidity which is not restricted to photophobia.

Animals↗

PubMed1986

Mesial prefrontal cortical lesions and timidity in rats. III. Behavior in a semi-natural environment.

Behavior of adult male rats with and without lesions in mesial prefrontal cortex (MFC) was studied in a large (72 m2) semi-natural environment (SNE) equipped with numerous wooden nest boxes. The experiment was conducted in 2 partial replicates, one in summer, one in mid-winter. Subjects were introduced to this environment 11 days after surgery, in groups. In the first replication, control and lesioned rats were subjected to mild food deprivation, beginning two weeks after introduction into the SNE. In the second replication, rats were first restricted to separate areas of the SNE, then later allowed full run of the environment. This procedure was then repeated. Summarizing the findings of both replicates, MFC rats were more likely to be found inside nest boxes than controls, changed nest boxes less often, and were less likely to obtain or hoard food from the daily feeding sessions, or to hoard and use nesting material. MFC rats were lower in social rank than controls, and lost less weight during the initial two weeks in replicate one, perhaps due to their relative inactivity. These differences waned over time when MFC rats were competing only within their group, but not when the brain damaged rats were forced to compete with intact controls. It is concluded that the timidity previously described in studies of MFC rats in a laboratory setting (Holson, Holson and Walker) has ethological validity, in that it is also evident in an SNE. The implications of these findings for an understanding of the evolution and function of prefrontal cortex are briefly discussed.

Animals↗

PubMedDate not supplied

Interactive effects of prenatal cocaine and nicotine exposure on maternal toxicity, postnatal development and behavior in the rat.

Two experiments were performed to investigate the interactive effects of prenatal coadministration of cocaine hydrochloride (C) and nicotine tartrate (N). Experiment I was designed to determine doses of C and N that could be coadministered without altering maternal gestational parameters and/or fetal viability. Exposure of Sprague-Dawley rats to combined high-dose C (20 mg/kg) and high-dose N (5.0 mg/kg) on gestation days 8-21 was not more toxic to dam or fetus that that of exposure to C alone. Experiment II investigated pregnancy outcome, postnatal development, and behavior of the offspring following drug exposure to either high-dose cocaine (20 mg/kg: CS), high-dose nicotine (5.0 mg/kg: NS), or both (NC) on gestation days 8-21. N was administered by osmotic minipump and C by sc injection. Saline-injected dams, fitted with saline-fitted pumps (SS), and untreated dams, pair-fed (PF) to NC females, served as controls. Alterations in maternal variables were limited to a 10-15% decrease in food consumption in NC and CS groups. Pregnancy outcome and birth statistics were unaffected by prenatal treatment, as was offspring body weight during the first four postnatal weeks. However, the development of surface righting was delayed inC CS pups, and only CS offspring were underresponsive to the stimulatory effects of dopamine agonists on activity and stereotypy. Behavioral responses to N challenge were similar in all groups. In addition, only CS offspring showed altered behavioral responses in a spontaneous alternation task. Treatment effects on dopamine D1 and D2 binding in the caudate nucleus were not observed. The combination of N and C did not exacerbate any of the behavioral changes seen in CS offspring. These results support the hypothesis that C is a behavioral teratogen in rodents, and suggest that in the present model, nicotine can mitigate some of the consequences of in utero exposure to cocaine.

Aging↗

PubMedDate not supplied

Prenatal haloperidol exposure: effects on brain weights and caudate neurotransmitter levels in rats.

Monoamines may exert a trophic effect on early brain development. To assess the role of dopamine in prenatal neurological development of the rat, haloperidol (HAL) was given in daily 2.5 or 5 mg/kg SC doses to dams over gestational days 6 to 20. This treatment regime did not enhance fetal mortality, but did produce reliable, if modest, stunting of the body and brain weight of offspring. The 5 mg/kg HAL dose consistently reduced offspring brain weight to roughly 90% of controls. This effect was probably permanent, in that it was seen throughout maturation and in adults as late as 140 days of postnatal age. Appropriate controls showed that this effect was not due to drug-induced reductions in food intake, to the presence of HAL in maternal milk, or to behavioral abnormalities in HAL-exposed dams. These effects had, at best, modest regional specificity, in that most brain regions were affected, independently of degree of dopaminergic innervation. Closer investigation of HAL effects on the striatum suggested that this permanent weight reduction was not accompanied by alterations in striatal concentrations of monoamines, monoamine metabolites, amino acids, choline, acetylcholine, DNA, protein, or water. It is concluded that prenatal HAL does stunt growth, but that this effect may not involve a direct drug influence restricted to the fetal dopamine system in the brain.

Acetylcholine↗

PubMedDate not supplied

Behavioral and neurochemical effects of prenatal methylenedioxymethamphetamine (MDMA) exposure in rats.

MDMA is a hallucinogenic drug that is used by the general public as a recreational drug of abuse. The neurobehavioral consequences of prenatal MDMA exposure are unknown. Groups of pregnant rats were gavaged with 0, 2.5, or 10 mg/kg MDMA during gestation on alternate gestational days 6-18. Gestational duration, litter size, neonatal birth weights and physical appearance at birth were unaffected by MDMA treatments. Pregnancy weight gain was significantly reduced by MDMA treatment. Progeny growth, maturational parameters (eye opening and incisor eruption times), surface righting reflex, swimming performance, forelimb grip strength, milk-induced behaviors, passive avoidance behavior, figure-8 maze activity over 48 hours, the density of brain serotonin (5-HT) uptake sites, and brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were unaffected by MDMA treatments. Olfactory discrimination on postnatal days (PND) 9-11 was enhanced in both male and female MDMA-treated progeny, while negative geotaxis (PND 7-10) was delayed in female pups. In contrast to progeny, MDMA caused dose-dependent decreases in 5-HT and 5-HIAA levels in discrete brain areas of the dam. It is concluded that prenatal exposure to MDMA at the levels used here produces only subtle behavioral alterations in developing rats. The dam is more at risk for MDMA-induced 5-HT depletion than is the conceptus.

3,4-Methylenedioxyamphetamine↗

PubMedDate not supplied

Euthanasia by decapitation: evidence that this technique produces prompt, painless unconsciousness in laboratory rodents.

Rapid euthanasia of laboratory rodents without the use of anesthesia is a necessary research technique whenever there is the likelihood of anesthesia or stress interfering with the chemistry of the tissues under investigation. Decapitation has long been the procedure of choice under such circumstances. Recently, however, the American Veterinary Medical Association (AVMA) panel on euthanasia recommended that decapitation be avoided on the grounds that the decapitated head may be conscious and suffering for as much as 15 seconds. The panel further recommended that if decapitation was scientifically necessary, the decapitated head be immediately immersed in liquid nitrogen. These AVMA guidelines now enjoy regulatory status; the recommendation that decapitation be avoided has thus caused considerable difficulty for all research requiring rapid, anesthesia-free collection of tissues. The scientific validity of these recommendations is consequently a matter of great practical as well as theoretical importance. The decision to discourage decapitation appears to have been based on a single literature report claiming that the EEG of the decapitated head revealed conscious suffering for more than 10 seconds (Mikeska and Klemm 1976). This review carefully examines the scientific literature on this subject. It is concluded that the report by Mikeska and Klemm of EEG activation in the decapitated head is correct, but that this phenomenon is also seen when the decapitated head is under deep anesthesia, and in normal brains under ether anesthesia or during REM sleep. Hence these findings do not demonstrate either consciousness or the perception of pain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Welfare↗

PubMedDate not supplied

Principles and pitfalls in the analysis of prenatal treatment effects in multiparous species.

Developmental studies often assess the effect of treatment of the pregnant mother on offspring. The use of multiparous species such as rats and mice in such studies creates a special set of design and analysis problems. These arise for two reasons. First, the availability of many offspring per litter tempts the experimenter to inflate sample size by treating scores from several pups per litter as independent observations. Second, large litter size seldom makes it practical to measure exposure effects in all offspring of an exposed dam. Such studies commonly involve two-stage sampling: Drawing a random sample of dams for treatment, then drawing a second sample of pups per dam for neurobehavioral measurements. In this article, such sampling was modeled by two different simulations. The first, a standard Monte-Carlo approach, sampled from random-normal distributions for litter mean and within-litter variability. The second simulation sampled without replacement from actual data on weight of all pups in a series of 39 nontreated rat litters. These mutually-supportive approaches demonstrate that litter effects, even over as few as three litters, are generally large and statistically meaningful. Consequently, statistical significance tests are sensitive to litter effects. Inflation of sample size by treating as few as 2 pups per litter as independent measurements can almost triple the nominal 0.05 alpha level. Furthermore, two-stage sampling increases the within-treatment error term and correspondingly reduces statistical power relative to one-stage sampling.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMedDate not supplied

The ontogeny of behavioral sensitization to phencyclidine.

Repeated exposure of adult rats to a variety of psychoactive compounds can result in altered behavioral responsiveness to later exposures depending on the dose, route, and frequency of administration and time of testing. The ontogeny and mechanism of this altered responsiveness are not well understood. To determine when behavioral sensitization to phencyclidine (PCP) occurs, neonatal and early developmental exposure effects of PCP were assessed on later behavioral responsiveness to a PCP challenge. Rat pups were injected daily for nine days beginning on either postnatal days (PNDs) 1 or 22 with 0.9% saline, 5.0 or 10.0 mg/kg PCP-HC1 (s.c.). Ten days following the last injection, rats were given one of the following drug challenges: 0.9% saline, 5.0 or 10.0 mg/kg PCP-HC1 (s.c.). Locomotor activity, ataxia, and several other behaviors were measured for 1 h beginning 2-3 min after the challenge injection. Two major findings emerged from these studies. First, pups treated subchronically with PCP on PNDs 1-9 did not exhibit any difference in behavioral sensitivity to a PCP challenge when tested on PND 19 compared to subchronically treated saline controls. In contrast, pups subchronically treated with PCP on PNDs 22-30 exhibited an increased sensitivity to the behavioral effects of a PCP challenge. These data suggest that PCP has age-dependent exposure effects that occur sometime after the first postnatal week and that result in an enhanced behavioral responsiveness to PCP later in life.

Animals↗

PubMedDate not supplied

Prenatal dexamethasone or stress but not ACTH or corticosterone alter sexual behavior in male rats.

Prenatal maternal stress in rats and mice can demasculinize and feminize the sexual behavior of adult male offspring. Causal mechanisms are unknown, but one attractive hypothesis is that stress activation of maternal adrenal glucocorticoid secretion is the responsible agent. To test this hypothesis, pregnant rats were exposed to a variety of substances which enhance glucocorticoid actions. These included ACTH (20 IU of a gel preparation, SC once daily), corticosterone (CORT; 7 mg/kg SC in oil, three times daily), or dexamethasone (DEX; 0.1 mg/kg, SC once daily). Controls included noninjected dams and a positive stress control group (restraint under bright lights three times daily). All treatments reduced maternal weight gain, DEX most potently. No treatment altered litter size, stillbirths, or sex ratio, but DEX reduced weight at birth, an effect still seen at postnatal day 85. DEX, CORT, and stress reduced male adrenal weight at birth, while DEX and CORT altered sexual differentiation as measured by anogenital distance. Stress impaired adult male sexual performance but not the lordosis quotient following exposure of animals to stud males. DEX affected both measures. No other treatment had any significant effect on sexual behavior. No treatment altered plasma LH levels, either basal or in response to an estrogen challenge in adult gonadectomized males. In adulthood there was no treatment effect on stress reactivity, measured behaviorally or by plasma glucocorticoids. Correlational analysis revealed that weight gain during pregnancy was the single best predictor of subsequent sexual performance. It is concluded that prenatal dexamethasone exposure demasculinizes and feminizes male offspring.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

PubMedDate not supplied

Postnatal methylazoxymethanol: sensitive periods and regional selectivity of effects.

Work on neonatal MAM exposure has focused primarily on exposure within the first week postpartum, and on resulting hypoplasia or stunting of the cerebellum. Rats in this study were exposed to MAM on 4 consecutive postnatal days (PND), beginning at one of six ages, from birth through weaning (PND 1, 5, 9, 13, 17, or 21). MAM was administered subcutaneously in doses of 3, 4, or 5 mg/kg twice per day. Rats were sacrificed at PNDs 28 or 84. The most sensitive age for MAM-induced stunting was determined to be PNDs 1-4. When 5 mg/kg MAM was administered twice daily on PNDs 1-4, body weight was reduced by 24% at age 28 days. Additionally, when compared to control rats, brains of the 28-day-old rats were stunted as follows: whole brain (11%), cerebellum (35%), hippocampus (11%), and olfactory bulb (27%). The effects of PND 1-4 MAM exposure were still evident at 84 days of age when cerebellum and olfactory bulbs from treated rats weighed 30% less than those same regions in control rats. These findings indicate that neonatal exposure to MAM results in permanent stunting in select regions of developing rat brain. This stunting, along with other known MAM effects, can be tailored by exposure age and dose to augment the use of MAM as a positive control for investigation of compounds with neurotoxic potential.

Age Factors↗

PubMedDate not supplied

Prenatal ethanol exposure in rats: long-lasting effects on learning.

Pregnant Sprague-Dawley rats were fed a liquid diet containing either 0% (group C), 18% (group L), or 36% (group H) ethanol-derived calories (EDC) from gestational day 1 to 20. Male offspring were assessed under a conditioned taste aversion paradigm (PND 35-45), in a complex maze (PND 68-80), and for operant behavior (temporal response differentiation and motivation to work for food, PND 140-198). Although conditioned taste aversion was fully acquired by all groups, retention of the conditioned taste aversion response was impaired in group H animals. Importantly, deficits in the acquisition of timing behavior were found in group H (group L not tested), confirming that this operant task is quite sensitive in detecting prenatal drug effects and demonstrating that neurological effects of prenatal ethanol exposure persist into late adulthood.

Animals↗

PubMedDate not supplied

Behavioral teratology and dominant lethal evaluation of nitrous oxide exposure in rats.

Epidemiological studies have suggested that spontaneous abortion may be increased in medical personnel following the sort of chronic low-level exposure to the anesthetic gas nitrous oxide (N2O) seen in surgical or dental operatories. These results are supported by some, but not all, animal studies, and results are less well established at low exposure levels. Behavioral effects in exposed animal offspring have also been observed, but again not in all studies. To further examine this problem, we conducted the present experiments. Adult male or female rats were exposed to trace concentrations of N2O (0%, 0.1%, 0.5%, or 1.0% in air) for 6 h daily either throughout gestation (females) or for 9 weeks (males). Offspring from treated adults were subjected to an extensive behavioral test battery. There were no clear dose-response effects on any of eight behavioural tests for any offspring. Maternal and offspring weights were normal from conception through adulthood. Additionally, we studied effects of N2O on male fertility by mating treated males with untreated females and examining uterine contents. There was no evidence for a substantial decline in fertility of exposed males, although there was a small dose-related trend for resorptions to increase and live births to decrease with increasing paternal N2O exposure. There results suggest that there is little alteration in male or female fertility following chronic exposure to low levels of N2O. There are also no significant long-term behavioral alterations in offspring exposed gestationally to trace levels of N2O via dam or sire.

Animals↗

PubMedDate not supplied

Functional effects of methylazoxymethanol-induced cerebellar hypoplasia in rats.

The behavioral effects of a series of methylazoxymethanol acetate (MAM) injections in neonatal rats were investigated. Pups were injected twice daily on days 5-8 after birth with 4 mg/kg MAM or saline. Similar treatment paradigms cause cerebellar hypoplasia, which is a result of a depletion of granule cells. MAM treatment reduced adult cerebellar weight to 92% that of control and was without effect on weight of other brain regions examined. Postweaning body weight gain in males was reduced. Nest odor preference and emergence (light/dark box) assessments indicated no significant effects. Complex maze assessments and performance in an operant test battery demonstrated no cognitive deficits. Indeed, MAM treated females performed better in a complex maze under lighted conditions than same-sex controls. Open field and running wheel activity levels in females were unaffected. Though not statistically significant, males exhibited a mild hyperactivity syndrome characterized by an increase in running wheel and open field activity, as well as a depressed startle response. Both sexes were hypersensitive to the locomotor-increasing effects of methamphetamine. These results suggest that the functional effects resulting from cerebellar hypoplasia produced by MAM treatment on PNDs 5-8 are milder than those resulting from MAM treatment beginning on the day of birth. The results are compared with other forms of cerebellar lesions and provide support for the hypothesis that early insult (day of birth or shortly after) produces hypoactivity whereas a later insult (day 4 or later after birth) produces a syndrome of hyperactivity.

Aging↗

PubMedDate not supplied

Retinoic acid exposure on gestational days 11 to 13 impairs swallowing in rat offspring.

We have previously reported that exposure to 10 mg/kg of all-trans-retinoic acid (RA) daily on the 11th, 12th, and 13th days of rat gestation is lethal to all fetuses so exposed, due to an inability to suckle [R.R. Holson et al., Neurotoxicol Teratol 19 (1997) 347-353]. Because this lethal RA effect could be due to any of a variety of causes, from olfactory problems in locating the nipple to a motor problem in sucking or swallowing, we performed the following experiment. Albino dams were exposed to 10-mg/kg RA or vehicle daily over gestational days (GDs) 11 to 13. On the afternoon of GD 21 all pups were delivered by c-section. Tongue cannulae were inserted into the oral cavity of these offspring, and used to infuse a solution of condensed milk directly into the mouth. During and after each of four infusions, the behavioral response to the infusion (typically rolling and curling) was recorded. Controls responded well to this procedure, typically swallowing all milk so infused. In contrast, almost no RA-exposed neonates were able to swallow milk infused into the oral cavity. In such cases the milk simply dribbled out of the mouth, while the stomach was found to be empty at autopsy. However, the RA-treated animals did seem aware that milk was entering their mouths, because they showed a normal behavioral response to milk infusion. We conclude that GD 11-13 retinoid lethality is due to motor not sensory problems in the control of swallowing.

Animals↗