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Biomedical subjects

W Slikker

Publications and source records attributed to W Slikker.

At least 145 records · Page 8Linked to original sources
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↗
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

Complex brain function in monkeys as a baseline for studying the effects of exogenous compounds.

We have examined the population characteristics of a group of 69 monkey subjects performing in a complex operant test battery designed to generate behaviors indicative of specific brain functions. These functions include learning, short-term memory and attention, time perception, position and color discrimination and motivation. Performance by a subject in one of these operant tasks is not necessarily correlated with or predictive of performance in the other tasks, indicating that the tests in the battery are monitoring the functions of different brain systems. Additionally, as demonstrated by challenging a few of the animals with intravenous delta-9-tetrahydrocannabinol, we have shown that the performances in the various components of the test battery are differentially sensitive to disruption by exogenous compounds.

Animals↗
PubMed1987

Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC).

Persistent behavioral effects resembling those of hippocampal brain lesions have been reported following chronic administration of marijuana or its major psychoactive constituent, delta-9-tetrahydrocannabinol (THC) to rats. We used morphometric techniques to investigate the effects of chronic THC on the anatomical integrity of the hippocampus. Rats dosed orally for 90 days with 10 to 60 mg/kg THC or vehicle were evaluated by light and electron microscopy up to 7 months after their last dose of drug. Electron micrographs revealed a striking ultrastructural appearance and statistically significant decreases in mean volume of neurons and their nuclei sampled from the hippocampal CA3 region of rats treated with the highest doses of THC. A 44% reduction in the number of synapses per unit volume was demonstrated in these same rats. Golgi impregnation studies of additional groups of rats treated with 10 or 20 mg/kg/day THC and sacrificed 2 months after their last treatment with THC revealed a reduction in the dendritic length of CA3 pyramidal neurons, despite normal appearing ultrastructure and no changes in synaptic density. The hippocampal changes reported here may constitute a morphological basis for behavioral effects after chronic exposure to marijuana.

Administration, Oral↗
PubMed1987

Fetal disposition of delta 9-tetrahydrocannabinol (THC) during late pregnancy in the rhesus monkey.

Three late-term (Gestational Days 146-151) rhesus monkeys were given 0.3 mg/kg delta 9-tetrahydrocannabinol (THC) intravenously via the maternal radial vein to quantify the placental transfer and fetal disposition of THC, the major psychoactive component of marijuana. Simultaneous blood samples were obtained from a maternal uterine vein and an intraplacental artery at 0, 3, 15, 30, 45, 60, 90, 120, and 180 min after dosing using an intraplacental cannulation technique. Samples of fetal plasma, spleen, testis, lung, brain, liver, bile, kidney, adrenals, thymus, and placenta were obtained at 180 min postdose. Samples were analyzed for THC and a major metabolite, 11-nor-9-carboxy-THC (11-nor), by radioimmunoassay (RIA). Peak plasma THC values were obtained 3 and 15 min after dosing in the mother (1419 ng/ml) and fetus (83 ng/ml), respectively. By 3 hr, maternal and fetal plasma THC levels were equal (37 ng/ml). Maternal plasma was sampled beyond 180 min at 24, 48, 72, and 96 hr postdose, times at which THC and 11-nor concentrations were either near or at the lower limit of sensitivity for the RIA (2 ng/ml). While maternal plasma 11-nor levels peaked at 1 hr (44 ng/ml), almost no 11-nor was detected in fetal plasma (less than 5 ng/ml). Fetal tissue concentrations of THC were 53 +/- 6 ng/g (SE) for brain and 114 +/- 10 ng/g for liver, while 11-nor was undetectable in placenta, fetal liver, and fetal brain. These data demonstrate that THC rapidly crosses the placenta and enters the fetus. The lack of 11-nor in fetal plasma and tissues suggests that this metabolite does not readily cross the placenta and that the fetus does not readily metabolize THC to 11-nor at this stage of development. A portion of this data was presented at the 1985 meeting of The American Society of Primatologists and at the 1986 meeting of The Teratology Society.

Animals↗
PubMed1987

Formation of artifactual metabolites of doxylamine following acid hydrolysis.

This study describes the use of gas chromatographic-mass spectrometric, high-performance liquid chromatographic and capillary column gas chromatographic separation techniques in demonstrating the production of several artifactual compounds reported in the literature as metabolites of doxylamine. Rhesus monkey urinary extracts which contained doxylamine and doxylamine metabolites were examined with and without acid hydrolysis. The production of 1-phenyl-1-(2-pyridinyl)ethanol and 1-phenyl-1-(2-pyridinyl)ethylene under acid hydrolysis conditions was demonstrated. These artifactual products were shown to originate from the acid hydrolysis of 2-[1-phenyl-1-(2-pyridinyl)ethoxy] acetic acid and not from doxylamine.

Animals↗
PubMed1987

Effects of chronic delta-9-THC treatment on cardiac beta-adrenoceptors in rats.

This study was designed to determine if chronic treatment with delta-9-tetrahydrocannabinol (THC) alters cardiac beta-adrenoceptors in the rat. Following daily oral administration of 10 or 20 mg/kg THC or an equivalent volume of control solvent for 90 days, rats were sacrificed, and sarcolemmal membranes were prepared from ventricular myocardium. Beta-adrenoceptor density and binding affinity estimated with (-)[3H]dihydroalprenolol; a beta-adrenergic antagonist, were not significantly affected by treatment with THC when compared to vehicle controls. These results suggest that the tolerance to cardiovascular effects of THC which develops during chronic exposure in the rat is not associated with alterations in cardiac beta-adrenoceptors as monitored by radiolabeled antagonist binding.

Animals↗
PubMed1987

The role of metabolism in the testing of developmental toxicants.

The delivery of potential developmental toxicants to the conceptus is dependent on several metabolic and pharmacokinetic factors. Within the maternal-embryo/fetal unit, maternal, placental, and embryo/fetal factors must be considered. These factors include blood flow, permeability, biotransformation, and elimination. Pharmacokinetic models based on data gathered from appropriate in vivo and in vitro studies may be used to describe the effect of these factors on toxicant delivery to the conceptus. Several known human developmental toxicants are discussed in terms of the metabolic and pharmacokinetic factors controlling their delivery to the conceptus. Metabolic events, including activation and/or detoxification, have been reported for the majority of the toxicants examined. Thus it would appear that the role of metabolism should be considered during the testing of potential developmental toxicants.

Animals↗
PubMed1987

Effect of trimethyltin on ornithine decarboxylase in various regions of the mouse brain.

Male C57B1/6N mice, 8-10 weeks old were given a single oral dose of 0, 1.0 or 3.0 mg/kg body weight of trimethyltin hydroxide (TMT). Levels of ornithine decarboxylase (ODC) activity were measured in several brain areas, 1, 2 and 7 days later. The lower dose of TMT produced a decrease of ODC in the caudate nucleus and hippocampus at all time points studied. Hypothalamus, cerebellum and brain stem levels of this enzyme were unaltered. At the higher dose of TMT, ODC activity in hippocampus, cerebellum and brain stem were increased relative to controls at 1 and 2 days after treatment, while other regions were not significantly affected. These elevated ODC levels returned to control values within 7 days. Thus, trimethyltin treatment causes changes in ODC activity in a region and dose-specific manner.

Animals↗
PubMed1986

Developmental toxicology of trimethyltin in the rat.

Pregnant rats were treated on either gestational day (GD) 7, 12, or 17 with single doses of trimethyltin chloride (TMT) ip at either 0, 5, 7, or 9 mg/kg. A significant effect of dose was manifest as decreased maternal weight at term, which persisted during lactation until postnatal day (PND) 15 in some groups. For all treatments combined, term weights of dams exposed on GDs 7 and 12 were greater than those treated on GD 17. Litter sizes were decreased for groups treated on GD 17 with 9 mg/kg TMT. Pups treated in utero and exhibiting treatment-induced decreases in weight at or near birth remained smaller than untreated animals into adulthood (PND 280). By PND 20, weights of pups treated on GD 7 greater than GD 12 greater than GD 17. Neuropathology of pups sacrificed on PND 1 was minimal in all animals with lesions only identified in animals treated on GDs 12 or 17 which consisted of subtle degenerative changes in the CA3 and CA4 regions of Ammon's horn of the hippocampus. Muscarinic cholinergic receptor binding in whole brains from pups on PND 1 did not show any significant changes compared to controls for any dose or day of exposure. These data indicate that prenatal TMT exposure results in postnatal toxicity in treated pups but only in the presence of maternal toxicity.

Animals↗
PubMed1986

Prenatal reserpine exposure in rats decreases caudate nucleus dopamine receptor binding in female offspring.

The effects of prenatal exposure to reserpine on [3H]spiroperidol binding in caudate nucleus at postnatal day (PND) 21 were investigated. Pregnant rats were dosed with 0, 0.375 or 0.750 mg/kg/day reserpine s.c. on days 12-15 of gestation. At PND 21, pups were killed and their brains were dissected and stored at -70 degrees C for analysis. Dopamine receptor binding was measured in membrane prepared from caudate nucleus of both sexes over a [3H]spiroperidol concentration range of 0.02 to 2.0 nM. Scatchard analysis revealed that the number of dopamine receptors (Bmax) in the membrane of female caudate nucleus was significantly decreased in a dose-dependent manner, while the dissociation constant (KD) was relatively unchanged. In male rats, neither Bmax nor KD was significantly reduced in either dose group. These results show that prenatal exposure to reserpine decreased the dopamine receptor number in caudate nucleus in a sex-dependent manner. This alteration may underly several sex-related behavioral changes that were previously found in offspring from identically treated dams.

Animals↗
PubMed1986

Cholinergic and dopaminergic alterations in the mouse central nervous system following acute trimethyltin exposure.

Male mice were given a single oral dose of 0, 1 or 3 mg/kg TMT-hydroxide and sacrificed 48 hrs, 1 and 2 weeks later. Brain areas were removed, dissected and frozen for later analysis of neurotransmitter receptor binding by filtration techniques and determination of concentrations of monoamines and their metabolites by HPLC/EC. Muscarinic cholinergic receptor binding was measured over a [3H]-quinuclidinyl benzilate (QNB) concentration range of 0.02 to 2.0 nM. Two days after TMT treatment, affinity of [3H]-QNB binding in frontal cortex increased. Gradual return to control binding affinity was seen over the next 2 weeks. The number of receptors decreased only at high dose after 1 week. In hippocampus, a similar increase was seen only at the 3 mg/kg dose after 1 and 2 weeks. Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were significantly decreased in the caudate nucleus 2 weeks after TMT treatment; concentrations of serotonin (5-HT), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were unaltered, nor was there a change in dopamine receptors as measured by [3H]-spiroperidol binding in the caudate nucleus or frontal cortex. To determine if TMT altered monoamine turnover or metabolite efflux, mice were dosed with 0 or 3 mg/kg TMT; 2 weeks later, pargyline (75 mg/kg, intraperitoneally) was administered and the mice sacrificed 0, 30 and 60 min. later. Monoamines and their metabolites were measured in caudate nucleus. The HVA elimination rate was unchanged. The data suggests that the lower concentrations of dopamine metabolites observed 2 weeks after TMT treatment were due to a decrease in dopamine turnover. The decrease in muscarinic receptor affinity in frontal cortex and hippocampus and the decrease in the rate of dopamine turnover in the caudate nucleus indicate that these 2 systems are affected by TMT and may participate in the expression of its toxicity.

Animals↗
PubMed1986

Transplacental metabolism of dexamethasone and cortisol in the late gestational age rhesus monkey (Macaca mulatta).

The synthetic glucocorticoid dexamethasone (DEX) and endogenous cortisol were compared in 2 groups of pregnant monkeys of gestational age 143-148 days. In group I, a fetal intraplacental vein and a maternal femoral vessel were catheterized. 3H-Cortisol and 14C-DEX were administered intravenously along with 0.2 mg/kg unlabelled DEX to the mother. Blood and tissue samples were collected to 3 h and urine and feces to 96 h. In group II, 4 of the 7 animals were predosed with DEX 10 mg/kg s.c. for 3 days prior to surgery. The fetus was removed by cesarean section and the in situ placenta was perfused via the umbilical arteries at 15 ml/min X 8 min with 3H-cortisol/14C-DEX in Hanks' balanced salt solution. Samples were taken from the umbilical vein and uterine vein. In group I, HPLC analysis of paired maternal and fetal plasma samples taken at 10, 20, 60, 120 and 180 min after dosing indicated that the F/M DEX ratio was significantly greater than the F/M cortisol ratio. In fetal lung and liver tissues analyzed, less than 2% of the cortisol remained unmetabolized by 3 h, whereas greater than or equal to 76% DEX remained as parent compound. There was no significant difference between the percentage of DEX (83 +/- 7%) and cortisol (73 +/- 3%) recovery in maternal urine and feces. In group II, HPLC analysis of paired umbilical vein and uterine vein samples at 2, 4 and 8 min showed that by 8 min 24% of cortisol was converted to cortisone by the uteroplacenta, but only 2.5% of DEX was converted to a metabolite. In DEX-pretreated animals both uterine vein and umbilical vein samples indicated an increase in cortisol to cortisone conversion. A significant increase in DEX metabolism was evident in the uterine vein samples but not the umbilical vein. These data indicate that the fetus is exposed to a higher proportion of DEX than cortisol and that the uteroplacenta plays a larger role in cortisol than in DEX metabolism. In addition, these data suggest that DEX pretreatment enhances the ability of the uteroplacenta to convert cortisol to cortisone.

Animals↗
PubMed1986

Early neurobehavioral and neurochemical alterations in rats prenatally exposed to imipramine.

Pregnant CD rats were treated subcutaneously with 0, 5 or 10 mg/kg/day of imipramine (IMI) on days 8-20 of gestation. Behavioral and neurochemical endpoints were measured at different postnatal days (PND). Three behavioral tests were conducted: negative geotaxis on PNDs 7-9; auditory startle habituation (ASH) on PNDs 14, 16 and 18; locomotor activity before and after intraperitoneal (i.p.) injection of saline or 0.5 mg/kg d-amphetamine on PND 21. Catecholamine levels, B-adrenergic and muscarinic cholinergic binding were measured on PND 1 and in PND 21 rats 3 hours after challenge. Maternal weight gained during the dosing period was decreased in a dose-related manner, but there were no dose-related differences in offspring body weights. On PND 7, low-dose males turned significantly sooner in negative geotaxic testing, and more high-dose males successfully turned (94%) than did controls (61%). A significant reduction in ASH amplitude was found only in males from the low-dose group on PND 18. IMI-exposed males tended to be more active prior to and following amphetamine challenge. On PND 1, male offspring from the low-dose group showed a 65% reduction in B-adrenergic receptor binding and a trend toward increased brain epinephrine (EPI) levels. On PND 21, no consistent dose-related receptor binding changes were observed. Cortical levels of EPI, however, tended to be higher in treated males and high-dose females challenged with d-amphetamine. These same rats also showed a marked elevation in locomotor activity following challenge with d-amphetamine. Thus, prenatal IMI exposure appeared to alter functional development of the central adrenergic systems in a complex manner, but one consistent with changes noted in both neurochemical and behavioral endpoints.

Analysis of Variance↗
PubMed1986

Fetomaternal kinetics of 14C-trimethyltin.

The mechanism of trimethyltin (TMT)-induced neuropathology remains unknown but likely relates to its time-course in the nervous system. To determine the pharmacokinetic profile of TMT in the fetomaternal unit, pregnant rats were injected on gestational day (GD) 17 with 7.0 mg/kg TMT plus 10 uCi 14C-TMT ip. Whole blood and plasma, cerebrum (CBR), cerebellum (CBE), and brainstem (BS) were sampled from mother and fetus/pup (f/p). Whole body saline perfusions of mother and f/p were performed independently to remove 14C contaminated blood. Whole blood total radioactivity showed f/p levels to be below maternal levels: at 4 hr, 42.6%, 24 hr, 54.2%, 96 hr, 64.8%. Litters were cross-fostered (CF) at birth with those from untreated mothers. Two weeks after treatment (postnatal day 10), pups exposed in utero (n=13, 2 litters) had whole blood 14C levels 13.9% that of their mothers. Untreated pups CF to treated mothers showed a blood concentration 1.8% of the dosed mother, indicating that TMT is transferred in milk. Radioactivity in maternal whole blood at 2 weeks was 49 +/- 11% (SEM) of peak (1 hr) levels. Only 2.5 +/- 0.2% of maternal whole blood radioactivity was present in plasma. 14C in urine accounted for 17.5 +/- 1.5% of the dose at 2 weeks (n=4). Both maternal and fetal brains contained about 2-4% as much radioactivity as found in maternal and fetal whole blood, respectively. TMT crosses the placenta, enters fetal blood and attains fetal brain levels that are equal to those found in maternal brain.

Animals↗
PubMed1985

Dexamethasone increases UDP-glucuronyltransferase activity towards bilirubin, oestradiol and testosterone in foetal liver from rhesus monkey during late gestation.

We previously showed that in perinatal rhesus monkeys hepatic UDP-glucuronyltransferase activities appear to develop differentially in two clusters, analogous to those of the rat. We demonstrate here that hepatic UDP-glucuronyltransferase activities differ between the rat and the rhesus monkey in their response to glucocorticoids. Treatment of pregnant rhesus monkeys with dexamethasone during late gestation increases UDP-glucuronyltransferase activities towards bilirubin, oestradiol and testosterone in the foetal-liver microsomal fraction to 25, 4 and 4 times their low control values respectively. Analogous dexamethasone treatment in rat fails to increase these activities significantly in the foetal liver. These findings suggest that maternal glucocorticoid therapy in late gestation could greatly increase the newborn primate's capacity to glucuronidate bilirubin.

Animals↗