Biomedical subjects

J M Fritschy

Publications and source records attributed to J M Fritschy.

126 records · Page 7Linked to original sources

PubMed1991

Efferent projections of different subpopulations of central noradrenaline neurons.

Early anatomical studies of the projections of central noradrenergic (NA) neurons led to the widely accepted view of NA cells as a class of diffusely projecting neurons. This view greatly influenced the formulation of numerous hypotheses about the functional role of these neurons in the central nervous system (CNS). With the introduction of transmitter-specific retrograde and anterograde transport methods, two powerful tools became available to rigorously re-examine whether the projections of NA neurons are diffuse or topographically organized. This article summarizes some of the results of these studies in which retrograde transport of fluorescent tracers and anterograde transport of the lectin Phaseolus vulgaris leucoagglutinin (PHA-L), respectively, were combined with immunohistochemical identification of NA neurons and their projections. The results of these studies revealed a remarkable degree of specificity in the projections of different subgroups of NA neurons. In the rat CNS, the differential distribution of NA axons of the locus coeruleus (LC) and non-coerulean NA cells is particularly striking in the spinal cord and brainstem. In these regions, NA axons of the LC are primarily distributed to sensory nuclei while NA axons of non-coerulean NA neurons are distributed to motor nuclei. The results support the proposition that NA neurons can be divided into subgroups which differ in their connections and hence represent separated anatomical entities with different functional capacities.

Animals↗

PubMed1991

Selective effects of DSP-4 on locus coeruleus axons: are there pharmacologically different types of noradrenergic axons in the central nervous system?

There is considerable evidence from biochemical studies that the transmitter-depleting action of drugs and neurotoxins which act upon central noradrenergic (NA) axon terminals is not uniform in different brain regions. Among NA axons, those originating in the locus coeruleus (LC) have been proposed to be most susceptible to the action of NA neurotoxins such as N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). The studies described here were conducted to determine whether this differential susceptibility to DSP-4 reflects a pharmacological heterogeneity between different populations of NA axons. To determine whether DSP-4 acts selectively upon LC axons, we have characterized the effects of this drug on NA axons in different brain regions, by using noradrenaline and dopamine-beta-hydroxylase (D beta H) immunohistochemistry. Following systemic administration of DSP-4, there was an almost complete loss of noradrenaline and D beta H staining in brain regions innervated by LC axons. No effects of the drug treatment were detected in brain regions innervated primarily by non-coerulean NA axons. These results demonstrate that both the transmitter-depleting and the neurodegenerative action of DSP-4 are restricted to NA axons originating in the LC. To explore the basis for this selectivity, noradrenaline uptake studies were conducted using synaptosomes from brain regions in which NA axons differ in their response to DSP-4. The results reveal a significant difference in the affinity of DSP-4 for the noradrenaline uptake carrier in cortical and hypothalamic synaptosomes. This finding is compatible with the hypothesis that the noradrenaline uptake carrier is pharmacologically distinct in LC and non-coerulean NA axons. This heterogeneity in noradrenaline uptake raises the question whether other drugs may also have differential actions on LC and non-coerulean NA neurons.

Adrenergic Agents↗

PubMed1990

Differential effects of DSP-4 on noradrenaline axons in cerebral cortex and hypothalamus may reflect heterogeneity of noradrenaline uptake sites.

The effect of the noradrenergic neurotoxin DSP-4 on high affinity transport of noradrenaline (NAT) was studied using rat brain synaptosomes. DSP-4 decreased NAT with the characteristics of a competitive inhibitor. The neurotoxin was more potent in inhibiting NAT into cortical synaptosomes (Ki = 179 +/- 39 nM) than into hypothalamic synaptosomes (Ki = 460 +/- 35 nM). Differences in NAT into cortical and hypothalamic synaptosomes were also observed with noradrenaline itself (Km = 39.5 +/- 7.5 nM and 100 +/- 12.1 nM, respectively) and with the catecholamine uptake blocker mazindol (Ki = 0.55 +/- 0.05 nM and 0.30 +/- 0.08 nM, respectively). The differences in the pharmacological properties of the noradrenaline uptake carrier in cerebral cortex and hypothalamus may account for the differential effects of DSP-4 on noradrenergic axons in these two brain regions.

Animals↗

PubMed1990

Distribution of two morphologically distinct subsets of serotoninergic axons in the cerebral cortex of the marmoset.

The serotoninergic innervation of the marmoset (New World monkey, Callithrix jacchus) cerebral cortex has been analyzed by using immunocytochemistry. The use of a sensitive monoclonal antibody against serotonin allowed the visualization of the fine morphology of individual axons. Two types of terminal axons were demonstrated: one has sparse, small, ovoid varicosities (dia. less than 1 micron), and the other has large, spheroidal varicosities (up to 5 microns in dia.), which are more densely clustered. The first type of axon is distributed through all cortical layers, with a characteristic laminar distribution that varies from area to area. The second type of axons was distributed sparsely in all regions but was markedly denser in the frontal and anterior parietal lobes, and in the hippocampal formation. Axons with large varicosities typically surrounded certain cell bodies and proximal dendrites, forming pericellular arrays, or baskets. These morphological specializations were most frequent in the frontal and anterior parietal cortex, where they were found around stellate and horizontal cells in layer I and around stellate and bipolar cells in layer II and III. Similar baskets were also found in the hippocampal formation, mainly along the border between the hilus and the granule cell layer of the dentate gyrus, across the CA4 field, and at each side of the pyramidal cell layer of the CA3 regions. The distribution and cellular morphology of the cell surrounded by the 5-HT basket fibres were suggestive of a subpopulation of interneurons, possibly GABAergic and/or peptidergic. In agreement with previous reports on the innervation of the cerebral cortex of other mammalian species, the marmoset cerebral cortex is innervated by two separate subsystems of serotoninergic axons. One of these may have a strong and specific influence on the cortical inhibitory circuitry, via relay through cortical interneurons.

Animals↗

PubMed1990

Distribution of locus coeruleus axons within the rat brainstem demonstrated by Phaseolus vulgaris leucoagglutinin anterograde tracing in combination with dopamine-beta-hydroxylase immunofluorescence.

Projections of the locus coeruleus (LC) to the midbrain and hindbrain were analyzed by anterograde transport of the lectin Phaseolus vulgaris leucoagglutinin (PHA-L). Following iontophoretic application of PHA-L into the LC, the distribution of labeled axons was analyzed in sections processed for the immunoperoxidase method and in sections processed for double-immunofluorescence staining using antibodies to PHA-L and to dopamine-beta-hydroxylase. This combined staining approach proved to be necessary for the unequivocal identification of LC axons in the brainstem since all injections labeled many non-noradrenergic axons whose distribution was different from that of LC fibers. The major new finding of the present study was the observation that large territories of the brainstem that receive a dense noradrenergic input are very sparsely innervated by the LC. Numerous labeled LC axons were observed in somatic afferent nuclei, tectum, pontine nuclei, interpenduncular nucleus, and inferior olivary complex. In contrast, very few labeled fibers were observed in autonomic and motor nuclei, and throughout the brainstem reticular formation, including raphe nuclei. Our data show that the distribution of LC axons in the brainstem is far less prominent than the projections of this nucleus to the forebrain and spinal cord. Our findings suggest that the dense NA projections to the core of the brainstem originate principally in non-LC NA neurons. On the basis of the present anatomical findings, a prominent role of the LC in motor and integrative functions of the brainstem appears unlikely.

Animals↗

PubMed1990

Demonstration of two separate descending noradrenergic pathways to the rat spinal cord: evidence for an intragriseal trajectory of locus coeruleus axons in the superficial layers of the dorsal horn.

The rat spinal cord receives noradrenergic (NA) projections from the locus coeruleus (LC) and the A5 and A7 groups. In contradiction to previous statements about the distribution of descending NA axons, we have recently proposed that in the rat LC neurons project primarily to the dorsal horn and intermediate zone, whereas A5 and A7 neurons project to somatic motoneurons and the intermediolateral cell column. The aim of the present study was to determine the funicular course and terminal distribution of descending NA axons from the LC and from the A5 and A7 groups. The organization of the coeruleospinal projection was analyzed by using the anterograde tracer Phaseolus vulgaris leucoagglutinin in combination with dopamine-beta-hydroxylase immunohistochemistry. The trajectory of A5 and A7 axons was studied in spinal cord sections of rats following ablation of the coeruleospinal projection with the neurotoxin DSP-4. To assess the relative contribution of the LC and the A5 and A7 groups to the NA innervation of the spinal cord, unilateral injections of the retrograde tracer True Blue were made at cervical, thoracic, and lumbar levels, and retrogradely labeled NA neurons were identified by dopamine-beta-hydroxylase immunofluorescence. The results of the anterograde tracing experiments confirm our previous findings that LC neurons project most heavily to the dorsal horn and intermediate zone. Analysis of horizontal sections revealed that LC axons descend the length of the spinal cord within layers I and II. In contrast to the intragriseal course of LC fibers, A5 and A7 axons travel in the ventral and dorsolateral funiculi and terminate in the ventral horn and the intermediolateral cell column. Retrograde transport studies indicate that the contribution of the A5 and A7 groups to the NA projection to the spinal cord is greater than that of the LC. We conclude that descending axons of the LC and A5 and A7 groups differ in their course and distribution within the spinal cord. The documentation of a definite topographic order in the bulbospinal NA projections suggests that the LC and the A5 and A7 groups have different functional capacities. The LC is in a position to influence the processing of sensory inputs, in particular nociceptive inputs, whereas A5 and A7 neurons are likely to influence motoneurons.

Animals↗

PubMed1989

Sample size and statistical power in the hierarchical analysis of variance: applications in morphometry of the nervous system.

Analysis of variance is commonly used in morphometry in order to ascertain differences in parameters between several populations. Failure to detect significant differences between populations (type II error) may be due to suboptimal sampling and lead to erroneous conclusions; the concept of statistical power allows one to avoid such failures by means of an adequate sampling. Several examples are given in the morphometry of the nervous system, showing the use of the power of a hierarchical analysis of variance test for the choice of appropriate sample and subsample sizes. In the first case chosen, neuronal densities in the human visual cortex, we find the number of observations to be of little effect. For dendritic spine densities in the visual cortex of mice and humans, the effect is somewhat larger. A substantial effect is shown in our last example, dendritic segmental lengths in monkey lateral geniculate nucleus. It is in the nature of the hierarchical model that sample size is always more important than subsample size. The relative weight to be attributed to subsample size thus depends on the relative magnitude of the between observations variance compared to the between individuals variance.

Aging↗

PubMed1989

Immunohistochemical analysis of the neurotoxic effects of DSP-4 identifies two populations of noradrenergic axon terminals.

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a potent and highly selective neurotoxin which induces degeneration of noradrenergic axons. The effects of DSP-4 vary considerably in different brain regions: the drug produces nearly complete depletion of noradrenaline in neocortex, hippocampus, cerebellum and spinal cord, but only partial depletion in hypothalamus and brainstem. In this study we have employed an immunohistochemical method to assess the neurotoxic effects of DSP-4 on the structural integrity of central noradrenergic neurons in the rat, and to identify those noradrenergic axons that remain in the central nervous system 2-4 weeks after DSP-4 treatment. The staining results identified noradrenergic axon terminals as the principal site of action of DSP-4; noradrenergic cell bodies and preterminal axons were not noticeably affected. DSP-4 produced an almost all or none neurotoxic effect on noradrenergic axon terminals in different brain regions. Nearly all noradrenergic axon terminals were destroyed in the neocortex, hippocampus, olfactory bulb, thalamus, tectum, cerebellum and spinal cord dorsal horn. In contrast, most noradrenergic axons were unaffected in the basal forebrain, hypothalamus, reticular formation, brainstem motor nuclei and spinal cord ventral horn. These remaining noradrenergic axon terminals differed morphologically from sensitive axons by their thickness, size and spacing of their varicosities and their dense arborizations within terminal fields. The distribution of noradrenergic axons susceptible to DSP-4 correlates very closely with the distribution of locus coeruleus axons and possibly all regions in which noradrenergic terminals are unaffected by DSP-4 receive their major noradrenergic input from non-locus coeruleus neurons. This study provides the first direct evidence that DSP-4 destroys noradrenergic axon terminals from the locus coeruleus, but not those from non-locus coeruleus neurons. This profound differential sensitivity of noradrenergic axons to DSP-4 is matched by distinct differences in their morphology and their topographic projections. The results support the view that locus coeruleus and non-locus coeruleus noradrenergic neurons constitute two separate subsystems, which differ not only in their projections but also with respect to the pharmacological properties of their axon terminals.

Animals↗

PubMed1989

Acute action of DSP-4 on central norepinephrine axons: biochemical and immunohistochemical evidence for differential effects.

Previous immunohistochemical studies of the long-term effects of the noradrenergic neurotoxin DSP-4 have demonstrated a remarkably selective vulnerability of norepinephrine (NE) axons of the locus coeruleus (LC). NE axons originating in non-LC NE neurons appear to be largely resistant to the neurotoxic action of DSP-4. We conducted this study to evaluate the acute effects of DSP-4 on NE axons in four different brain regions: cerebral cortex, cerebellum, ventral forebrain, and hypothalamus. NE levels were determined by high-performance liquid chromatography (HPLC) 6 and 24 hr and 14 days after DSP-4 administration. NE axons in these brain regions were visualized in brain sections at 6 and 24 hr after drug treatment, using a specific antiserum to NE. HPLC assays revealed profound reductions of NE levels in cerebral cortex and cerebellum, but only minor decreases in ventral forebrain and hypothalamus. NE immunohistochemistry showed dramatic differences in the acute effects of DSP-4 on NE axon staining: nearly complete loss of staining in cortex and cerebellum, in contrast to an almost unchanged staining pattern in ventral forebrain and hypothalamus. This study demonstrates that NE immunohistochemistry is a valuable tool to assess the acute effects of DSP-4 on NE axons in different brain regions. The results provide the first direct evidence that NE axons are not uniformly acted on by DSP-4 and suggest that the acute effects of DSP-4 are restricted to LC axons.

Animals↗

PubMed1989

The noradrenergic neurotoxin DSP-4 eliminates the coeruleospinal projection but spares projections of the A5 and A7 groups to the ventral horn of the rat spinal cord.

Systemic administration of the noradrenergic neurotoxin DSP-4 results in a complete loss of staining of noradrenergic (NA) axons in the dorsal horn and intermediate zone of the rat spinal cord. NA axon staining in the ventral horn and in the intermediolateral cell column is only slightly decreased by the drug treatment. We have taken advantage of this differential effect of DSP-4 on NA axons to determine the location and number of cells that give rise to NA axons in the ventral horn and the intermediolateral cell column. Retrograde transport of the fluorescent tracer True blue was combined with dopamine-beta-hydroxylase immunohistochemistry 2 weeks after treatment of rats with 50 mg/kg of DSP-4. Compared with controls, the drug treatment resulted in a more than 90% decrease in the number of retrogradely labeled NA neurons in the locus coeruleus and an only 30-50% reduction in the number of retrogradely labeled NA cells in the A5 and A7 groups. The results reveal different sites of termination in the spinal cord of NA axons originating in the LC and in NA cells of the A5 and A7 groups: the LC distributes fibers mainly to the dorsal horn and the intermediate zone, while NA cells of the A5 and A7 groups project to motoneurons of the ventral horn and the intermediolateral cell column.

Animals↗

PubMed1988

Neurotoxic effects of p-chloroamphetamine on the serotoninergic innervation of the trigeminal motor nucleus: a retrograde transport study.

The rat forebrain receives projections from both dorsal and median raphe nuclei. It has recently been shown that serotoninergic axons arising from the dorsal raphe nucleus, but not those from the median raphe nucleus, degenerate following systemic administration of p-chloroamphetamine (PCA). The present study was conducted to determine (i) whether the motor nucleus of the trigeminal nerve is innervated by overlapping projections from multiple serotonin cell groups and (ii) whether a particular subset of serotoninergic axon terminals in the trigeminal motor nucleus are sensitive to the neurotoxic effects of PCA. Retrograde transport was used in combination with immunofluorescence to identify the serotonin-positive cells that project to the trigeminal motor nucleus both in control rats and in rats previously treated with PCA. In untreated rats, an average of 95 retrogradely labeled serotonin-positive neurons were found in the dorsal raphe nucleus, 135 in the nucleus raphe obscurus, 132 in the nucleus raphe pallidus and 63 in the ventrolateral medulla. After treatment with PCA, there was a marked decrease (-77%) in the number of retrogradely labeled serotoninergic neurons in the dorsal raphe nucleus, whereas the number of labeled neurons was unchanged in the raphe obscurus and raphe pallidus. These results demonstrate that PCA selectively lesions serotonin axon terminals arising from the dorsal raphe nucleus, while sparing projections from the raphe obscurus and raphe pallidus to the trigeminal motor nucleus. This conclusion is in agreement with previous findings that in the forebrain only axons from the dorsal raphe are vulnerable to PCA. The data provide further evidence that serotoninergic axons originating in the dorsal raphe nucleus differ from other serotoninergic axons in their pharmacological properties and that the dorsal raphe may contain a functionally unique subset of serotonin neurons.

Amphetamines↗

PubMed1988

Serotoninergic system in the brainstem of the marmoset: a combined immunocytochemical and three-dimensional reconstruction study.

The distribution and morphology of serotoninergic neurons in the marmoset (New-World monkey) brainstem were studied by immunocytochemistry and computer-assisted three-dimensional reconstruction. The cytoarchitectonic localization of serotoninergic neurons was ascertained in series of adjacent immunostained and Nissl-stained sections, and the extent and shape of the serotoninergic nuclei were visualized by computer reconstruction. The overall distribution of the immunoreactive neurons is comparable to that already described for several species of primates. The serotoninergic nuclei are spatially well segregated into an anterior and a posterior group. The anterior group, in the mesencephalon and the rostral pons, contains the largest population of serotoninergic neurons. These neurons are not confined to the raphe nuclei near the midline, but rather expand laterally in the reticular formation. This expanded distribution of the neurons in the anterior group results in a partial fusion of the nuclei. In some nuclei, particularly the median raphe, subdivisions can be clearly delineated on the basis of the distinct morphology of the neurons and of their clustering. The neurons of the posterior group, in the caudal pons and the medulla, are almost all contained within the limits of the raphe nuclei. The serotoninergic neurons located in the reticular formation form a lateral column, which is clearly separated from the serotoninergic neurons found near the midline. Immunoreactive axons are distributed throughout the brainstem, but they innervate certain motor and sensory nuclei more densely. It was consistently found in newborn animals that the overall immunoreactive axonal network was richer than in juveniles or adults, suggesting that there may be a major modification in the function of the serotoninergic system around birth.

Animals↗

PubMed1988

Postnatal development of dendrites of relay neurons in the lateral geniculate nucleus of the marmoset (Callithrix jacchus): a quantitative Golgi study.

Dendrites of multipolar relay neurons in the lateral geniculate nucleus of the marmoset (Callithrix jacchus), at various ages from birth to adulthood, were studied in rapid Golgi preparations. The dendrites were analyzed by means of three-dimensional computer reconstructions and decomposed into intermediate and terminal segments, both of which were further classified according to their centrifugal order. Measurements were made of the number of segments per dendrite, the total length of dendrites, and the mean length of intermediate and terminal segments. In adult marmosets, there are four stem dendrites on average per neuron, and each dendrite divides into a mean of 14 segments. Between birth and 6 weeks of age, the mean dendritic length doubles, mainly because of changes in terminal segments. There is a significant decrease in dendritic length into adulthood. The total number of stem dendrites does not change after birth, but during the first postnatal week dendrites lose distal segments, after which there is a significant increase in the number of segments of orders 3 to 7. The mean length of intermediate segments does not change with age, nor with order, whereas the length of terminal segments increases from 50 to 120 microns from birth to 6 weeks of age, and then decreases to the adult value of 80 microns. In conclusion, during the period of most rapid visual development, important morphological changes occur in geniculate relay-cell dendrites, involving essentially terminal segments. These observations correlate well with changes of geniculate volume and neuronal density.

Animals↗

PubMed1987

Distribution of locus coeruleus axons in the rat spinal cord: a combined anterograde transport and immunohistochemical study.

The distribution of locus coeruleus axons in the rat spinal cord was studied by anterograde transport of Phaseolus vulgaris leucoagglutinin in combination with dopamine-beta-hydroxylase immunohistochemistry. Locus coeruleus axons were observed primarily in the superficial laminae of the dorsal horn. Few locus coeruleus fibers were seen in the vicinity of motoneuron pools or in the intermediolateral cell column of the thoracic spinal cord. The results of this study suggest a selective action of the coeruleo-spinal projection upon sensory inputs to the spinal cord.

Animals↗

PubMed1986

Quantitative changes in morphological parameters in the developing visual cortex of the marmoset monkey.

Several quantitative morphological parameters were measured during postnatal development in area 17 of the marmoset monkey (Callithrix jacchus). In a series of 14 animals, at ages from birth to adulthood, we studied changes in the thickness, surface area and volume of area 17, as well as the neuronal and glial numerical densities, and total numbers. We found evidence for a rapid increase in thickness, area and volume, culminating between 6 weeks and 6 months postnatally, and then decreasing. The adult values are close to those observed in one-month-old animals. The overshoot in thickness and volume is greatest in layers II, III, IVa and IVc. The neuronal density shows a trend which is opposite to that of volume, and therefore the total number of neurons is constant postnatally, ca. 38 million neurons in area 17 of one hemisphere. The number of glial cells approximately doubles during the first postnatal month and remains stable afterwards, so that in the adult, there is one glial cell for two neurons. Morphological development of area 17 in this New World monkey is similar to that reported in Old World monkeys, as are the adult values for neuronal and glial densities.

Animals↗

PubMed1986

Postnatal development of quantitative morphological parameters in the lateral geniculate nucleus of the marmoset monkey.

Quantitative morphological parameters were studied in the lateral geniculate nucleus (LGN) of the marmoset monkey (Callithrix jacchus) during development, using a series of 14 animals, at ages from birth to adulthood. They include the volume of the LGN and of its layers and interlaminar zones, their neuronal content expressed as numerical density and total number, and the density and number of glial cells in the nucleus as a whole. The volume of the LGN increases rapidly after birth, reaches a maximum at 6 months of age, and then decreases to its adult value of about 11 mm3. Neuronal density follows a reciprocal curve, reaching an adult value of about 41,000 neurons/mm3, so that the total number of about 440,000 neurons per LGN remains constant throughout life although large interindividual variations, especially in juveniles, do not allow unequivocal statements about total neuronal number to be made. Parvocellular layers occupy most of the geniculate volume, and contain about 74% of its neurons in the adult. We found no difference in their development pattern compared with the magnocellular component. The 'superficial' layers and interlaminar zones contain more than 15% of the geniculate neurons, and they could therefore play an important functional role in the primary visual pathway of New World primates. The number of glial cells nearly triples during the first 6 weeks and stabilizes around 800,000 in the LGN of one hemisphere. As the same brains were used as in a previous study on the area 17 of the marmoset (Dev. Brain Res., 29 (1986) 173-188) direct comparisons of the development of cortex and thalamus can be made. Their development is parallel in time, and in both cases the adult values for volume, neuronal density and glial numbers are reached several months postnatally.

Animals↗

PubMedDate not supplied

Immunobiochemical characterization of the NMDA-receptor subunit NR1 in the developing and adult rat brain.

To investigate the developmental and regional expression of the NR1-subunit of the NMDA-receptor on the protein level, two polyclonal antisera [NR1(N) and NR1(C)] were raised against fusion proteins derived from the N- and C-terminal domain of the NR1-subunit, respectively. In Western blots of rat brain membranes, both antisera specifically recognized a single protein band with an apparent molecular size of 115 kDa. The regional distribution of the NR1-subunit immunoreactivity was analyzed in the developing and adult rat brain using sections blotted onto nitrocellulose membranes for immunostaining. With the NR1(N)-antiserum, strongest signals were detected in hippocampus, followed by cortex, striatum and thalamus, and weaker staining was observed in tectum, brainstem and cerebellum of adult brain. The NR1(C)-immunoreactivity exhibited a similar distribution, except that the staining in thalamus, tectum, brainstem and cerebellum was faint or virtually absent. The distinct pattern of NR1(N)- and NR1(C)-immunoreactivity arose during postnatal development. At birth, moderate staining with both NR1-subunit antisera was observed throughout the brain increasing strongly in most brain regions until postnatal day 21. In some brain areas, however, the NR1(C)-, in contrast to the NR1(N)-staining, decreased postnatally e.g. in thalamus, tectum and brainstem. The restricted staining intensity of the NR1(C)-antiserum in particular areas of adult and developing brain appears to reflect the emergence of C-terminal splice variants of the NR1-subunit which are not recognized by the NR1(C)-antiserum.

Animals↗

PubMedDate not supplied

The response of noradrenergic axons to systemically administered DSP-4 in the rat: an immunohistochemical study using antibodies to noradrenaline and dopamine-beta-hydroxylase.

The response of noradrenaline (NA) axons to the effects of systemic injections of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was studied in the rat brain. Antibodies to NA and to dopamine-beta-hydroxylase (DBH) were employed to assess by immunohistochemistry the effects of DSP-4 on NA axons between 6 h and 2 weeks after drug administration. The changes in NA and DBH staining after DSP-4 treatment were restricted to brain regions innervated by the locus coeruleus. In these areas, DSP-4 induced profound loss of both NA and DBH from NA axons, but with a distinctly different time-course. While NA disappeared within hours after drug treatment, DBH staining of NA axons remained unchanged during the first 4 days after DSP-4 treatment. Thereafter, there was an abrupt loss of DBH staining which coincided with the appearance of numerous brightly stained, thick and swollen NA axons. The distribution of these fibres suggests that they represent the distal ends of preterminal NA axons. Two weeks after drug treatment, NA axons could no longer be visualized by either NA or DBH immunohistochemistry in regions affected by DSP-4. During this 2-week time-period, the staining of cell bodies in the locus coeruleus and of ascending NA axons in the dorsal bundle was unaffected. The results suggest two phases in the response of NA axons to DSP-4: an acute phase, marked by loss of transmitter, and a neurodegenerative phase, characterized by loss of DBH and structural disintegration of NA axons.

Animals↗