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R T Robertson

Publications and source records attributed to R T Robertson.

At least 73 records · Page 4Linked to original sources
PubMed1989

Intraocular injections of tetrodotoxin reduce transiently expressed acetylcholinesterase activity in developing rat visual cortex.

Geniculo-recipient layers of primary visual cortex in the rat display a transient pattern of acetylcholinesterase (AChE) activity during the second postnatal week of life. Previous work has demonstrated that neonatal enucleations markedly reduce the transient AChE activity in visual cortex. The present studies were undertaken to determine the effects of reduced afferent neural activity on expression of the transient pattern of AChE activity. Rat pups received intraocular injections of tetrodotoxin (TTX) on postnatal days (PND) 3, 5, 7, 9 and 11 and were sacrificed on PND 12. Some animals were enucleated on PND 3. Brain sections were processed for AChE histochemistry and analyzed by optical densitometry. These experiments show that uniocular injections result in a markedly decreased level of AChE activity in layer IV of the medial part of cortical area 17 contralateral to the injected eye. The degree of reduction of AChE activity from repeated TTX injections was similar to the degree of reduction following enucleation on PND 3. Binocular injections of TTX result in a reduction of AChE activity in layer IV throughout cortical area 17, similar to the effects of binocular enucleation on PND 3. Experiments combining injection of horseradish peroxidase along with TTX on PND 11 demonstrate that retinal ganglion cells of TTX injected eyes are still capable of anterograde axonal transport. These data demonstrate that normal innervation and afferent activity are necessary for the transient expression of AChE activity by geniculocortical neurons.

Acetylcholinesterase↗
PubMed1989

Embryotoxicity studies of norfloxacin in cynomolgus monkeys: I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys.

Norfloxacin, a new orally active antibiotic, was investigated in cynomolgus monkeys for potential developmental toxicity. Fifty-seven monkeys were administered a control vehicle or norfloxacin by nasogastric gavage during the major period of organogenesis on gestational days (GD) 21 through 50 at doses of 0, 50, 100, 150, or 200/300 mg/kg/day. There was no evidence of teratogenicity at any dose level. Maternotoxicity and a significant increase in embryolethality occurred following doses of 200/300 mg/kg/day. The maternotoxicity was not expected based on range-finding studies in nonpregnant female monkeys, which showed no signs of toxicity in doses up to 500 mg/kg/day. Additional studies were conducted to determine if norfloxacin caused similar toxicity later in gestation. Forty-six pregnant monkeys were dosed with a control vehicle or 200 mg/kg/day norfloxacin for one of three 10-day periods on GD 36-45, 71-80, or 111-120. There were no maternotoxic, embryotoxic, or fetotoxic effects observed. Plasma concentrations of norfloxacin in five cynomolgus monkeys following 50 and 200 mg/kg oral doses were not dose-proportionate. However, at a given dose, administered in cross-over fashion, plasma concentrations of norfloxacin were higher in nonpregnant females (approximately 20-40%) than during pregnancy when the same subject was compared. At the no-observed-effect dose for maternal and embryotoxicity (50 mg/kg), peak plasma concentrations of norfloxacin in pregnant cynomolgus monkeys are approximately threefold higher than those observed in human volunteers receiving norfloxacin at the maximum recommended therapeutic dose of 400 mg (5.7 mg/kg based on 70 kg body weight) twice per day.

Animals↗
PubMed1989

Effects of ivermectin on reproduction and neonatal toxicity in rats.

In this study we describe the effects of ivermectin (MK-0933) on the reproduction and neonatal toxicity of several generations of rats. Ivermectin was administered orally at dose levels of 0.05, 0.1, 0.2, 0.4, 1.2 or 3.6 mg/kg body weight/day. An increase in postnatal pup mortality up to approximately day 10 post-partum and a decrease in pup weights in the surviving offspring compared with those of the control groups indicated that ivermectin was toxic to neonatal rats at doses as low as 0.4 mg/kg body weight/day. Cross-fostering of the rats indicated that the neonatal toxicity was related not to in utero exposure but to postnatal exposure through maternal milk. Subsequent studies with tritiated ivermectin administered orally to rats showed that levels of radioactivity in maternal milk were 3-4-fold higher than those in the plasma, which resulted in significantly higher levels of ivermectin in the brain and plasma of nursing offspring. The period of enhanced neonatal sensitivity (up to approximately day 10 post-partum) correlates with increases in the plasma-brain ratios of total radioactivity in offspring from approximately 1 on day 4 post-partum to approximately 3 on day 10 post-partum. This is consistent with the postnatal formation of the blood-brain barrier in the species. In other mammalian species, including humans, sheep and rabbits, the blood-brain barrier is formed pre-natally. Therefore, the neonatal toxicity of ivermectin in rats is probably the result of a combination of excessive exposure through maternal milk and the increased permeability of the blood-brain barrier during the early postnatal period in this species.

Animals↗
PubMed1988

Investigations of the origins of transient acetylcholinesterase activity in developing rat visual cortex.

Transient acetylcholinesterase (AChE) activity is characteristic of cortical area 17 of the developing laboratory rat during the second and third postnatal weeks of life. This AChE activity is most intense in a band that corresponds to cortical layer IV and the deep part of layer III, but also is found in the outer half of cortical layer I and in layer VI. The morphology of the pattern of the histochemical reaction product indicates that the transient AChE is characteristic of an axonal terminal field. The present report describes results of 3 sets of experiments aimed at determining the source of transient AChE in cortical area 17. First, placement of lesions in portions of the basal forebrain or in the cingulate bundle results in a decrease in the general pattern of AChE throughout occipital cortex and especially in layer I, but the transient bands of AChE in layers III-IV of cortical area 17 are not eliminated. Second, kainic acid or cobalt chloride injections in cortical area 17 result in the loss of many AChE-positive neuronal somata but do not eliminate the transient pattern of AChE in thalamo-recipient layers of cortical area 17. Similarly, treatment of fetuses with mitotic inhibitors that eliminate many of the neurons destined for granular and supragranular layers does not eliminate transient patterns of AChE. Third, lesions that include the lateral geniculate nucleus of the thalamus or geniculocortical projections result in a marked loss of the pattern of AChE in thalamo-recipient layers of cortical area 17, without significant loss in other layers of area 17 or in other regions of occipital cortex. These data support the hypothesis that the transient AChE found in thalamo-recipient layers of cortical area 17 is contained within geniculocortical axon terminals.

Acetylcholinesterase↗
PubMed1988

Development of 'non-specific' cholinesterase-containing neurons in the dorsal thalamus of the rat.

In adult rats, neurons displaying histochemical staining for 'non-specific' cholinesterase (ChE) are found 3 distinct regions of the dorsal thalamus: the thalamic reuniens nucleus (Re), the anterior dorsal nucleus (AD), and a region that includes the lateral part of the central lateral nucleus (CL) and the ventral portion of the lateral dorsal nucleus (LD). Normal development of ChE-positive neurons was studied with cholinesterase histochemical techniques in postnatal infant rats. Although ChE staining of capillary endothelium is detectable shortly after birth, ChE staining of neurons first occurs at about postnatal day 5 (PND 5) with light staining of AD and CL-LD. At PND 7, staining in AD and CL-LD has increased in intensity and staining also is present in neurons of the anterior ventral (AV) and ventral anterior (VA) nuclei. ChE staining of neurons in Re first appears at PND 10. The number of neurons staining for ChE in each of these nuclei, and also the intensity of staining in individual neurons, appear to increase during the next several days until about PND 14. After PND 14, ChE staining intensity in neurons of AD, Re, and CL-LD appears to plateau and the pattern of staining continues into adulthood. In contrast, ChE staining of neurons in VA declines markedly and only a very few neurons in the dorsal part of VA remain ChE-positive after PND 21. ChE staining of neuropil in AV increases markedly, obscuring somatal staining in this nucleus. These results are discussed in regard to transient and continued expression of ChE activity in the dorsal thalamus and possible functional roles of ChE.

Acetylcholinesterase↗
PubMed1988

Neonatal enucleations reduce specific activity of acetylcholinesterase but not choline acetyltransferase in developing rat visual cortex.

Infant rats were subjected to unilateral or bilateral enucleation or sham lesions on the day of birth. On postnatal day 13 or 14, tissue blocks from cortex were assayed for acetylcholinesterase (AChE) and choline acetyltransferase (ChAT). Bilateral enucleation resulted in a decrease in specific activity of AChE in occipital cortex, as compared with control animals. Unilateral enucleation resulted in a decrease of AChE activity in the hemisphere contralateral to the enucleated orbit. However, neither type of enucleation resulted in significant changes of ChAT specific activity. These data suggest that reductions in AChE activity resulting from neonatal enucleations are not due to a direct involvement of cholinergic afferents to visual cortex.

Acetylcholinesterase↗
PubMed1987

Organization of subcortical pathways for sensory projections to the limbic cortex. I. Subcortical projections to the medial limbic cortex in the rat.

Subcortical afferent projections to the medial limbic cortex were examined in the rat by the use of retrograde axonal transport of horseradish peroxidase. Small iontophoretic injections of horseradish peroxidase were placed at various locations within the dorsal and ventral cingulate areas, the dorsal agranular and ventral granular divisions of the retrosplenial cortex and the presubiculum. Somata of afferent neurons in the thalamus and basal forebrain were identified by retrograde labeling. Each of the anterior thalamic nuclei was found to project to several limbic cortical areas, although not with equal density. The anterior dorsal nucleus projects primarily to the presubiculum and ventral retrosplenial cortex; the anterior ventral nucleus projects to the retrosplenial cortex and the presubiculum with apparently similar densities; and the anterior medial nucleus projects primarily to the cingulate areas. The projections from the lateral dorsal nucleus to these limbic cortical areas are organized in a loose topographic fashion. The projection to the presubiculum originates in the most dorsal portion of the lateral dorsal nucleus. The projection to the ventral retrosplenial cortex originates in rostral and medial portions of the nucleus, whereas afferents to the dorsal retrosplenial cortex originate in caudal portions of the lateral dorsal nucleus. The projection to the cingulate originates in the ventral portion of the lateral dorsal nucleus. Other projections from the thalamus originate in the intralaminar and midline nuclei, including the central lateral, central dorsal, central medial, paracentral, reuniens, and paraventricular nuclei, and the ventral medial and ventral anterior nuclei. In addition, projections to the medial limbic cortex from the basal forebrain originate in cells of the nucleus of the diagonal band. Projections to the presubiculum also originate in the medial septum. These results are discussed in regard to convergence of sensory and nonsensory information projecting to the limbic cortex and the types of visual and other sensory information that may be relayed to the limbic cortex by these projections.

Afferent Pathways↗
PubMed1987

Organization of subcortical pathways for sensory projections to the limbic cortex. II. Afferent projections to the thalamic lateral dorsal nucleus in the rat.

Afferent projections to the thalamic lateral dorsal nucleus were examined in the rat by the use of retrograde axonal transport techniques. Small iontophoretic injections of horseradish peroxidase were placed at various locations within the lateral dorsal nucleus, and the location and morphology of cells of origin of afferent projections were identified by retrograde labeling. For all cases examined, subcortical retrogradely labeled neurons were most prominent in the pretectal complex, the intermediate layers of the superior colliculus, and the ventral lateral geniculate nucleus. Labeled cells were also seen in the thalamic reticular nucleus and the zona incerta. Within the cerebral cortex, labeled cells were prominent in the retrosplenial areas (areas 29b, 29c, and 29d) and the presubiculum. Labeled cells were also seen in areas 17 and 18 of occipital cortex. Peroxidase injections in the dorsal lateral part of the lateral dorsal nucleus result in labeled neurons in all of the ipsilateral pretectal nuclei, but especially those that receive direct retinal afferents. Labeled cells were also seen in the ventral lateral geniculate nucleus and the rostral tip of laminae IV-VI of the superior colliculus. In contrast, peroxidase injections in ventral medial portions of the lateral dorsal nucleus result in fewer labeled pretectal cells, and these labeled cells are found exclusively in the pretectal nuclei that do not receive retinal afferents. Other labeled cells following injections in the rostral and medial portions of the lateral dorsal nucleus are seen contralaterally in the medial pretectal region and nucleus of the posterior commissure, and bilaterally in the rostral tips of laminae IV and V of the superior colliculus. Camera lucida drawings of HRP labeled cells reveal that projecting cells in each pretectal nucleus have a characteristic soma size and dendritic branching pattern. These results are discussed with regard to the type of sensory information that may reach the lateral dorsal nucleus and then be relayed on to the medial limbic cortex.

Afferent Pathways↗
PubMed1987

A morphogenic role for transiently expressed acetylcholinesterase in developing thalamocortical systems?

Experiments in infant rats have revealed patterns of intense acetylcholinesterase (AChE) activity in primary sensory thalamic nuclei and thalamocortical recipient zones of primary sensory areas of cerebral cortex. The distribution and appearance of AChE staining indicates that the transient AChE in these areas is characteristic of thalamocortical neurons. The patterns of AChE are detectable during the first postnatal week of life, reach peak intensity during the second postnatal week, and decline to normal adult levels by the end of the third postnatal week. These temporal parameters correlate well with the time of thalamocortical axon growth into the cerebral cortex. These data suggest that the transient AChE may be playing a morphogenic role in the development of thalamocortical connections.

Acetylcholinesterase↗
PubMed1987

'Non-specific' cholinesterase-containing neurons of the dorsal thalamus project to medial limbic cortex.

Thalamocortical neurons that contain 'non-specific' cholinesterase (ChE) were studied with cholinesterase histochemistry and experimental axonal tracing techniques in adult rats. In addition to the presence of ChE that is ubiquitous in capillary endothelium, neurons that contain ChE are found in 3 distinct regions of the dorsal thalamus, the thalamic reuniens nucleus (Re), the anterior dorsal nucleus (AD) and a region that includes the lateral part of the central lateral nucleus (CL) and the ventral portion of the lateral dorsal nucleus (LD). ChE activity appears light in cerebral cortex in general but histochemical staining is slightly greater in neuropil of the cingulate gyrus. Anterograde transport techniques with autoradiography demonstrated that neurons in the LD-CL region project to anterior cingulate cortex and the dorsal retrosplenial area. Anterograde degeneration techniques demonstrated that AD projects primarily to ventral retrosplenial cortex. Injections of horseradish peroxidase (HRP) in the anterior cingulate cortex resulted in double labeled cells (cells containing both ChE and HRP reaction products) primarily in LD and CL. HRP injections into ventral retrosplenial cortex resulted in double labeled cells in AD and Re. HRP injections in the subiculum resulted in double labeled cells in Re. Lesions placed in the region of thalamocortical projections resulted in a loss of ChE in the ipsilateral cingulate gyrus, as measured both histochemically and enzymatically. The finding that neurons containing ChE project to medial limbic cortex suggests that the ChE may be involved in the function of the thalamocortical component of the limbic system.

Animals↗
PubMed1987

Electron microscopic localization of acetylcholinesterase in the dentate gyrus of young and adult rats.

Acetylcholinesterase (AChE) histochemical staining occurred in neurons of the dentate gyrus at the day of birth and steadily increased in intensity and distribution during the first 3 postnatal weeks until the adult pattern was reached. Granule cells failed to display AChE staining; however, the somata of most non-principal cells in these regions showed AChE activity. It is interesting that most hilar neurons in the dentate gyrus were AChE-positive, but molecular layer local circuit neurons and pyramidal basket cells associated with the granule cell layer did not display AChE staining. AChE reaction product was localized to the nuclear envelope and cisternae of the granular endoplasmic reticulum in the labeled neuronal somata. In addition, the neuropil in the dentate gyrus displayed AChE staining associated with membranes. The possible cholinoceptive role of the AChE somata in the hilus is discussed.

Acetylcholinesterase↗
PubMed1987

Effects of neonatal monocular and binocular enucleation on transient acetylcholinesterase activity in developing rat visual cortex.

Geniculo-recipient layers of visual cortical area 17 in the laboratory rat display a transient pattern of acetylcholinesterase (AChE) activity during the second and third postnatal weeks of life. The appearance of the AChE histochemical reaction product and its distribution in thalamic recipient layers of cortical area 17 suggest that this transient AChE serves as a marker for the region of geniculocortical axon terminals. In the present study, infant rats were enucleated monocularly or binocularly on the day of birth. Animals were sacrificed at postnatal days 5-21. Frozen sections cut in either the transverse plane or parallel to the pial surface were processed for AChE histochemistry. Neonatal monocular enucleation resulted in a marked reduction of transient AChE activity in thalamic recipient layers of the medial part of area 17 contralateral to the enucleated orbit, i.e., the monocular segment of area 17. No loss of AChE was observed in area 17 ipsilateral to the enucleation. Pigmented and albino strains of rats did not differ significantly in the extent to which monocular enucleation reduced the transient AChE in contralateral visual cortex. Neonatal binocular enucleation resulted in an almost complete loss of AChE histochemical staining in thalamic recipient layers throughout cortical area 17, without loss of AChE in other cortical regions. These data support the hypothesis that transient AChE serves as a marker for the region of geniculocortical axon terminals, and also demonstrate that the transient expression of AChE in visual cortex depends upon normal innervation or activity of the geniculocortical neurons.

Acetylcholinesterase↗
PubMed1987

Evaluation of the teratogenicity and pharmacokinetics of diflunisal in cynomolgus monkeys.

This study examined the pharmacokinetics and potential teratogenicity of the nonsteroidal antiinflammatory drug, diflunisal, in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered 0.5% methyl cellulose, 20 mg/kg/day diflunisal, or 80 mg/kg/day diflunisal on Days 25 to 48 of gestation. There was no evidence of maternal toxicity, increased abortion rate, fetal growth retardation, or malformation. These data demonstrate that diflunisal is not teratogenic in cynomolgus monkeys over a dosage range of 20 to 80 mg/kg/day. Peak plasma levels of diflunisal were found 1 hr after oral administration of [14C]diflunisal at a dosage of 60 mg/kg and declined to low levels by 24 hr. The plasma elimination half-life was calculated to be 10.2 hr over the period of 1 to 8 hr postadministration. Intact diflunisal accounted for 96.4% of total plasma radioactivity at 0.5 hr and declined to a value of 74% at 8 hr. Plasma protein binding averaged greater than 99% over a concentration range of 62.5 to 250 micrograms/ml. Urinary excretion of diflunisal and metabolites averaged 66.5% of the dosage over the first 4 days postadministration, compared with 0.8% in the feces. The majority of activity represented conjugates of diflunisal. Embryo concentrations of diflunisal on Days 35 to 37 of gestation were 0.7 and 1.1% of maternal plasma level at 4 hr postadministration of 20 or 60 mg/kg, respectively.

Abnormalities, Drug-Induced↗
PubMed1986

Distribution of 'non-specific' cholinesterase-containing neurons in the dorsal thalamus of the rat.

This report describes the distribution of histochemically identified 'non-specific' cholinesterase (ChE)-containing neurons in the dorsal thalamus of the rat. Juvenile or young adult Long-Evans or Sprague-Dawley rats were sacrificed by formalin perfusion. Some animals received systemic injections of 1.5-2.0 mg/kg DFP 4-24 h prior to sacrifice. Separate series of 50 micron frozen sections were processed for cholinesterase histochemistry using acetylthiocholine, butyrylthiocholine, or propionylthiocholine as substrates. Adjacent sections processed with each of the 3 substrates allowed comparison of the distributions of neurons containing the histochemical reaction products. Neurons containing moderate to high concentrations of ChE reaction product were found in 3 distinct regions of the dorsal thalamus. First, neurons staining intensely for ChE were found in a cluster that corresponds to the thalamic reuniens nucleus. Second, a cluster of neurons staining intensely for ChE was found in a region that included the lateral part of the central lateral nucleus and extended laterally into the ventral-lateral part of the lateral dorsal nucleus. Third, moderate ChE staining was observed in the neurons of the anterior dorsal nucleus. Of these regions, only the anterior dorsal nucleus shows moderate to high levels of acetylcholinesterase. The function of ChE in normal brain function is unknown. It is particularly interesting, however, that the thalamic nuclei containing ChE-positive neurons send thalamocortical projections to the medial limbic cortex, including cingulate, retrosplenial and subicular cortices.

Acetylcholinesterase↗
PubMed1986

Effects of neonatal monocular enucleation on the number of GAD-positive puncta in rat visual cortex.

Rats that had one eye removed on the day of birth were examined at various postnatal ages with immunocytochemical methods to determine the effect on the development of the GABAergic axonal plexus in the visual cortex. The monocular segment of visual cortex contralateral to the enucleated orbit had 20-30% fewer GABAergic axon terminals than the monocular segment of visual cortex contralateral to the normal eye. Other cortical areas did not show any significant changes. These findings suggest that sensory deprivation of the visual cortex interferes with the normal development of GABAergic neurons.

Animals↗
PubMed1986

Association between adverse maternal and embryo-fetal effects in norfloxacin-treated and food-deprived rabbits.

Norfloxacin is a new antibiotic which caused embryo-fetal toxicity in association with maternotoxicity when given orally to rabbits at 100 mg/kg/day. The intestinal flora of rabbits is unusually sensitive to many antibiotics and it was suspected that the maternotoxicity and embryo-fetal toxicity caused by oral norfloxacin were secondary to an effect on the intestinal flora. To test this idea, a teratologic study was conducted in which rabbits were dosed on Days 6 to 18 of gestation with norfloxacin given orally at 100 mg/kg/day or subcutaneously at 20 mg/kg/day. The oral treatment caused decreased food consumption (to less than 15 g/day in some animals), body weight loss, an increased resorption rate, and decreased fetal weight. Among the females in the orally dosed group, there was a significant correlation (p less than or equal to 0.005) between the effects on maternal body weight and the resorption rate. The subcutaneous treatment caused little intestinal exposure (biliary excretion = only 2-4% of dose) and no maternotoxicity or embryo-fetal toxicity, even though blood levels of drug were at least as high as those in the oral group. Since the maternotoxicity and embryo-fetal toxicity were specific to the oral route and not correlated with the level of systemic exposure, the maternotoxicity may have been secondary to an effect on the intestinal flora and the embryo-fetal toxicity may have been secondary to the maternotoxicity. The decreased food consumption observed in the oral group may have contributed to the embryo-fetal toxicity since, in a separate study, it was found that lowering the amount of food provided to rabbits on Days 6 to 18 of gestation from 150 g/day to 50 or 15 g/day also caused adverse maternal and fetal effects including, at 15 g/day, fetal malformations.

Animals↗
PubMed1985

Transient patterns of acetylcholinesterase activity in visual cortex of the rat: normal development and the effects of neonatal monocular enucleation.

This paper describes the normal development and disappearance of acetylcholinesterase (AChE) activity in layer IV of rat visual cortex and the effects of neonatal monocular enucleation on this transient pattern of AChE activity. Subjects were laboratory-born male or female Long-Evans rats. Some animals underwent monocular enucleation within 6 h of birth. Animals were sacrificed at various ages and AChE activity was detected histochemically in tissue sections. AChE activity is first detectable histochemically in visual cortex area 17 as a fine fiber-like plexus in layer IV at about 7 postnatal days of age. The intensity of the staining increases during the second postnatal week and reaches peak intensity at days 12-14. The intensity of the AChE staining in layer IV of area 17 appears to decrease during the third postnatal week and the dense AChE band disappears by postnatal day 21. The distribution of AChE in layer IV of area 17 corresponds closely to the field of termination of geniculocortical projections and the fiber-like pattern of AChE activity resembles the appearance of an axonal terminal field. Neonatal monocular enucleation results in a marked decrement in the spatial extent of the AChE activity in layer IV of cortical area 17. The AChE-positive plexus is lost in the medial regions of area 17 contralateral to the enucleated eye. AChE activity remains in the lateral part of area 17, probably corresponding to that part of area 17 innervated by secondary projections from the intact ipsilateral eye. The functional role of this transient AChE activity is unknown. The present data suggest that AChE activity is characteristic of geniculocortical axon terminals during the period of time in which they are establishing functional connections with postsynaptic sites in cortex.

Acetylcholinesterase↗