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Biomedical subjects

J Luthman

Publications and source records attributed to J Luthman.

At least 37 records · Page 2Linked to original sources
PubMed1997

Trimethyltin exposure in the rat induces delayed changes in brain-derived neurotrophic factor, fos and heat shock protein 70.

Trimethyltin chloride (TMT) treatment in adult rats leads to limbic brain lesions that are detectable with classical neuropathological techniques 3 days after exposure. In particular, the hippocampal cells of the CA3c region are affected. The temporal and regional characteristics of TMT toxicity as reflected in changes of activity-dependent factors were studied in adult male Sprague-Dawley rats using quantitative in situ hybridization and immunohistochemistry. No significant alterations in the BDNF mRNA were detected in hippocampus and cerebral cortex 1 and 4 h after 8 mg TMT/kg. Three days after TMT, a significant increase in BDNF mRNA was detected in CA1, and increases in BDNF mRNA were also seen in cortical layers. An increase in BDNF hybridization signal was seen over scattered neurons within and outside CA3c at 3 days. Four h after 8 mg TMT/kg, BDNF immunoreactivity was reduced in the pyramidal cells of the CA3c and CA1 regions as well as in the dentate gyrus. No significant change in BDNF immunoreactivity was seen in hippocampus or cerebral cortex 3 days after TMT. BDNF interacts with the high-affinity receptor tyrosine kinase B (trkB). No immediate alteration in trkB mRNA was seen in hippocampus or cerebral cortex after 8 mg TMT/kg, while at 3 days trkB mRNA was significantly reduced in the CA3c pyramidal cell layer. No changes could be detected in neurotrophin-3 mRNA at either 1, 4 h or 3 days after TMT. Three days after 8 mg TMT/kg, a major induction of hsp70 mRNA occurred in a subset of neurons in the CA3c region, concomitant with an increased expression of c-fos mRNA as well as Fos protein in the hilar region of hippocampus. Hence, an early and transient decrease in BDNF appears to occur after TMT exposure, which is succeeded at 3 days by increases in BDNF, c-fos and hsp 70 mRNAs, concomitant with a decrease in trkB mRNA in regions known to be vulnerable to TMT. These results demonstrate that TMT causes a delayed, spatially restricted increase in activity-dependent gene expression, making TMT-induced disturbances an interesting model of neurodegenerative events.

Animals↗
PubMed1996

Effects of neonatal dopamine depletion on sensory inhibition in the rat.

Central dopamine systems appear to play an important role in sensory information processing. In particular, the filtering (or gating) of repetitive auditory stimuli is modulated by pharmacological manipulations that affect dopaminergic neurotransmission. The present study further addressed the role of dopamine in auditory gating. Three-day-old male Sprague-Dawley rats, pretreated with desipramine, received intracisternal injections of 6-hydroxydopamine (6-OHDA; 75 micrograms in 10 microliters) or the vehicle. At 4 months of age the rats were implanted for evoked potential recording and auditory gating was assessed using a paired click paradigm. Neonatally administered 6-OHDA did not alter gating in the adult rats. However, unlike for the control group, systemic amphetamine (1.83 mg/kg, IP) failed to disrupt gating in the treated rats. Apomorphine (1.0 mg/kg, SC) disrupted gating in both groups. Neonatal 6-OHDA treatment caused significant reductions in dopamine levels in the striatum, nucleus accumbens, and substantia nigra/ventral tegmental regions. There was an inverse relationship between substantia nigra/ ventral tegmental area dopamine levels and auditory gating. Overall, the results suggest that amphetamine-induced auditory gating loss requires presynaptic dopamine release, but that the deficiency occurs through postsynaptic dopamine receptor activation.

Animals↗
PubMed1995

Transient changes in Fos and GFAP immunoreactivity precede neuronal loss in the rat hippocampus following neonatal anoxia.

Early and delayed neuronal and glial changes in the hippocampus were studied in Wistar rats following neonatal anoxia induced by 100% N2 exposure for 25 min at approximately 30 h postnatally. Sham-treatment induced a transient increase in the number of fos immunoreactive neurons in the CA1, CA2, and CA3 regions, with a peak at 120 min following handling. In contrast, a significant decrease in the number of fos-stained cells was seen in the CA1 and CA2 regions at 120 min after the exposure to anoxia, compared to sham-treatment. At 150 and 240 min increased fos immunoreactivity was detected in the CA2 region of anoxic rats. Enhanced glial fibrillary acidic protein staining was seen at Postnatal Day 7 (P7) in the hippocampus of the rats exposed to neonatal anoxia, while no differences between anoxic and sham-treated animals were observed at later time-points. No alteration in nerve cell density was found at P7, while at P15 and later stages a significant reduction in neuronal density was seen in the CA1 region of anoxic rats. Thus, the rapid induction in hippocampal neuronal activity that followed sham-treatment was blocked by the neonatal anoxia, as revealed by changes in immediate early gene expression. A transient reactive astrocytosis developed in the days after the anoxic insult, followed by a loss of neurons in the CA1 region. The findings indicate that a sequence of specific neuronal and glial alterations takes place in the hippocampus after neonatal anoxia, which finally leads to a detectable, regionally restricted, neuronal loss. Moreover, inhibition in fos protein expression may be an early marker for the anoxic damage in CA1 neurons.

Animals↗
PubMed1995

Short-term effects of perinatal asphyxia studied with Fos-immunocytochemistry and in vivo microdialysis in the rat.

In the present study, the short-term consequences of various perinatal asphyctic periods were studied at the peripheral and CNS levels in the rat. Perinatal asphyxia was induced in rat pups delivered by caesarean section within the last day of gestation, by placing the uterus horns including the fetuses in a water bath at 37 degrees C for various periods of time (0-23 min). Following asphyxia, the uterus horns were opened. The pups were then removed and stimulated to breathe. Subcutaneous levels of pyruvate (Pyr), lactate (Lact), glutamate (Glu), and aspartate (Asp) were monitored with microdialysis 40 min after delivery. In parallel experiments, the pups were sacrificed 80 min after delivery. The brains were removed, fixed, cut, and processed for Fos immunocytochemistry. The number of Fos-immunoreactive (IR) cells in different brain structures was counted under light microscopy. Subcutaneous levels of Pyr, Lact, Glu, and Asp increased following perinatal asphyxia, as compared to caesarean-delivered pups or to spontaneously delivered controls. A maximum increase in Pyr levels (approximately threefold) was observed with 2-3 min of asphyxia, while Lact levels increased along with the length of asphyxia. A maximum increase in Glu and Asp levels (approximately threefold) was observed with 10-11 min of asphyxia. Fos-IR nuclei were predominantly found in the piriform cortex, and in the cortical amygdaloid complex. In some cases, mainly in pups exposed to asphyxia, Fos-positive cells were also seen in other tele-diencephalic structures.

Amino Acids↗
PubMed1995

Hyperactivity in neonatally dopamine-lesioned rats requires residual activity in mesolimbic dopamine neurons.

Neonatal destruction of mesencephalic dopamine (DA) neurons in rats through administration of 6-hydroxydopamine (6-OHDA; 75 micrograms IC) leads to locomotor hyperactivity at adulthood. Treatment with the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine (H44/68; 250 mg/kg) was shown to reduce the motor activity of neonatally 6-OHDA-lesioned rats to activity levels similar to controls. In both animal groups, DA and metabolite tissue levels decreased after the H44/68 treatment. However, the extent of the H44/68-induced DA decrease was less pronounced in the 6-OHDA-lesioned animals, with no change at all in the dorsal striatum. These results imply that residual activity in mesolimbic DA neurons is required for maintaining the hyperactivity seen after neonatal 6-OHDA lesions, and that this hyperactivity is apparently mediated by postsynaptic alterations.

Animals↗
PubMed1995

The use of the rat iris as a model system to evaluate the effect of the cholinotoxin, AF64A, in vivo.

The iris is innervated by both cholinergic parasympathetic, and adrenergic sympathetic branches of the autonomic nervous system. This innervation represents a simple and anatomically well-defined system to evaluate the effects of chemical compounds on cholinergic and adrenergic neurons. AF64A (acetyl ethylcholine aziridinium) is a known cholinotoxin in the brain and, in these experiments using the iris system, we evaluated its in vivo effect on cholinergic enzyme activity, pupillary size, and catecholamine neurotransmitter levels. We found in this system that AF64A reduces the activity of choline acetyltransferase (ChAT) but not acetylcholinesterase (AChE). AF64A is selective for cholinergic neurons, since norepinephrine and dopamine levels were unaffected.

Acetylcholinesterase↗
PubMed1995

Time-course of trimethyltin effects on the monoaminergic systems of the rat brain.

The normalization of certain behavioral functions after a trimethyltin (TMT) insult indicates that compensatory processes may occur (Paule and McMillan, 1986; Bushnell and Angell, 1992). The monoamine (MA) neurons are known to be sensitive to TMT, however, a detailed temporal description of the effects is lacking. One week after TMT exposure, 8 mg/kg i.p. to adult male Sprague-Dawley rats, the levels of serotonin (5-HT) and noradrenaline (NA) were decreased in several brain regions, whereas the levels of dopamine were unaltered. In addition, a reduced density of 5-HT immunoreactive fibers was seen in hippocampus and cortex. The lesion in the serotonergic and noradrenergic systems was followed by a recovery. Twelve weeks after TMT treatment, 5-HT and NA levels were increased in hippocampus, and 5-HT levels in striatum. In cerebellum, NA, 5-HT and 5-HIAA levels were decreased at 12 weeks. Compensatory processes led to recovered levels of 5-HT and NA in all regions but cerebellum, although regionally specific increases developed with time possibly due to hyperinnervation. Inhibition of the aromatic amino acid decarboxylase with NSD1015 yields accumulation of catecholamine and 5-HT precursors. Two weeks after TMT, levels of 5-HTP and L-dopa were not different in the TMT-treated rats as compared to controls, indicating that TMT does not affect MA synthesis.

Animals↗
PubMed1994

NGF increases neuritic complexity of cholinergic interneurons in organotypic cultures of neonatal rat striatum.

The influence of NGF on cholinergic interneurons in organotypic roller tube cultures of 4 day postnatal rat striatum was examined after 13 to 16 days in vitro. Cultures were divided into four groups. The medium of the NGF treated group was supplemented with 5 ng/ml NGF, whereas control groups were cultured either without NGF, by adding 20 ng/ml neutralising anti-NGF antibody, or by adding both NGF and anti-NGF antibody to the medium. Two different cell populations were identified by an image analysis system which measured acetylcholinesterase staining intensity. It was demonstrated that NGF promotes survival of the large, intensely stained population. Eighty computer-assisted reconstructions of intensely stained cells, 20 for each treatment group, were performed in a random order by means of a neuron tracing system. Axons and dendrites were analysed separately. NGF enhanced complexity of neuritic, predominantly axonal trees by increasing the number of axonal segments by 91% to 100% (P < 0.01), the number of dendritic segments by 33% to 63% (P = 0.09 to P < 0.01), maximal axonal branch order by 37% to 50% (P < 0.05), and maximal dendritic branch order by 22% to 37% (P < 0.05). Further evidence of more complex neuritic trees was given by Sholl concentric sphere analysis. Anti-NGF antibody could block all these effects. General rules of branching architecture were not affected by NGF treatment as shown by analysing mean segment length in relation to the branch order, branch point exit angles, total tortuosity, Rall's ratio, and tapering of neuritic trees.

Acetylcholine↗
PubMed1994

Trimethyltin-induced expression of GABA and vimentin immunoreactivities in astrocytes of the rat brain.

Adult Sprague-Dawley rats were given a single dose of trimethyltin chloride (TMT). Three days following treatment, a neuronal alteration was observed in the CA3c pyramidal cell layer of hippocampus which was not accompanied by any apparent astrocyte reaction. At 1 as well as 2 weeks after treatment, a gliosis in hippocampus, piriform, and entorhinal cortices was detected by glial fibrillary acidic protein (GFAP) immunohistochemistry. Concomitant with the enhanced astrocytic GFAP, astrocytes were swollen and expressed immunoreactivity to vimentin and gamma-aminobutyric acid (GABA). The astrocytic GABA immunoreactivity may reflect a trimethyltin-induced alteration in astrocyte phenotype, or alterations in compartmentalization and/or metabolism of GABA.

Animals↗
PubMed1994

Alterations in central monoamine systems after postnatal lead acetate treatment in rats.

The present study was undertaken to investigate the effects of postnatal lead exposure on central monoamine systems. Newborn male Sprague-Dawley rats were given 1 or 8 mg/kg lead acetate intraperitoneally for 20 days postnatally. Two groups of control rats received sodium acetate, or sodium acetate in oversized litters to compensate for lead-induced malnutrition in the high lead dose group, while nontreated animals also served as controls. At Day 21 or 51 regional tissue levels of monoamines were determined using HPLC techniques. No major changes were seen after the lead exposures in the levels of dopamine, noradrenaline, and serotonin, or metabolites of dopamine and serotonin, when compared to respective control groups. On the other hand, in the control group given sodium acetate in over-sized litters some alterations of the monoamine levels were observed in frontal cortex and striatum at Day 21 compared to controls. At Day 51, the striatal homovanillic acid and 5-hydroxyindoleacetic acid levels were higher in the low lead dose group compared to those in the controls. No other changes in the monoamine levels were seen at Day 51. At 50-70 days postnatally, potassium-stimulated dopamine overflow was studied in striatum with in vivo chronoamperometry. In the high lead dose group the amplitudes of signals were lower in both the dorsal and ventral striatum compared to the controls, while no difference was seen in the clearance time of dopamine. The capacity of the dopamine terminals to respond to repeated stimulation was not affected by the lead exposure. Thus, the steady-state levels of monoamines were essentially unaltered after postnatal lead exposure in rats, while functional aspects of striatal dopamine transmission were affected after exposure to the higher dose of lead. These findings support the hypothesis that lead-induced changes in motor skills and exploratory behavior may be related to altered dopamine neurotransmission.

Adolescent↗
PubMed1994

Unilateral neonatal intracerebroventricular 6-hydroxydopamine administration in rats: I. Effects on spontaneous and drug-induced rotational behaviour and on postmortem monoamine levels.

6-Hydroxydopamine (6-OHDA; 100 micrograms in 5 microliters) was injected into the right ventricle (intracerebroventricular, ICV) of 3-day old Sprague-Dawley rats in an attempt to produce a unilateral neonatal dopamine (DA) lesion. At adult stage, the rats were studied for spontaneous, handling- and drug-induced rotational behaviour. The 6-OHDA-treated rats showed hyperreactivity at handling, in the animal facility and in the experimental sets. This behaviour was not observed in vehicle-treated rats, and it did not decrease through the successive experiments. Apomorphine (0.05-1 mg/kg, SC) and caffeine (20 mg/kg SC) produced contralateral rotation in neonatal 6-OHDA, but not in vehicle-injected rats. d-Amphetamine (0.2-2 mg/kg, SC) produced strong, dose-dependent, ipsilateral rotation, while the serotonin (5-HT) releasing agent, p-chloroamphetamine (2 mg/kg, SC) produced a short-lasting and weak ipsilateral rotation in the 6-OHDA-treated rats. On the 6-OHDA-injected side, DA and metabolites levels were reduced by > 70-90% in the striatum, the nucleus accumbens and the tuberculum olfactorium, while in the mesencephalon a 50% decrease was found. On the contralateral side, restricted decreases in DA and metabolites were observed. Noradrenaline (NA) levels were decreased bilaterally in the forebrain. In contrast, 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were increased in the ipsilateral striatum (> 180%), and tuberculum olfactorium (> 120%). Thus, neonatal unilateral ICV 6-OHDA administration produced a significant unilateral decrease in tissue levels of DA and metabolites, which was most marked in the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Unilateral neonatal intracerebroventricular 6-hydroxydopamine administration in rats: II. Effects on extracellular monoamine, acetylcholine and adenosine levels monitored with in vivo microdialysis.

6-hydroxydopamine (6-OHDA, 100 micrograms in 5 microliters) was injected into the right ventricle of 3-day-old Sprague-Dawley rats in order to produce a unilateral dopamine (DA) lesion. At adult stage, the rats were implanted with microdialysis probes into the left and right striata. On the injected side, basal extracellular levels of DA were reduced by > 65%, as compared to the contralateral side or to the levels found in vehicle-injected rats. Extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced by > 95%, while acetylcholine (ACh) was decreased by > 50%. d-Amphetamine (2 mg/kg SC) produced a 10-fold increase in extracellular DA levels in the striatum contralateral to the 6-OHDA-injected side, while on the ipsilateral side. DA levels were not affected by d-amphetamine. d-Amphetamine produced an increase (> 2 fold) in extracellular ACh levels, on both ipsilateral and contralateral sides. Choline and adenosine levels were unaffected by any of the experimental conditions. Thus, neonatal unilateral ICV administration of 6-OHDA produced an ipsilateral decrease in striatal extracellular DA, DOPAC and HVA levels, compared to the contralateral side. A reduction of extracellular ACh levels was also observed on the 6-OHDA-injected side. The DA releasing effect of d-amphetamine was abolished on the 6-OHDA-injected side, but not that on ACh levels, indicating that striatal DA and ACh d-amphetamine-induced release are produced by independent mechanisms in the neonatally unilateral 6-OHDA-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

The morphine sparing effect of diclofenac sodium following caesarean section under spinal anaesthesia.

We have studied the morphine sparing effect of a single 100 mg diclofenac sodium suppository following elective caesarean section performed under spinal anaesthesia. Fifty patients randomly allocated into a placebo or an active group were compared. There was a statistically significant (P < 0.05) reduction in total morphine consumption and in consumption calculated as mg kg h(-1) in the diclofenac group, although pain scores were comparable in the two groups.

Journal Article↗
PubMed1993

In vivo electrochemical measurements of exogenous dopamine clearance in normal and neonatal 6-hydroxydopamine-treated rat striatum.

The regulation of extracellular dopamine (DA) levels was studied in rat striatum after neonatal dopamine lesions and enhanced serotonin (5-HT) fiber ingrowth, induced with 6-hydroxydopamine (6-OHDA). We used rapid in vivo chronoamperometry combined with local DA applications. DA was pressure ejected in doses of 5 to 100 pmol at a distance of approximately 300 microns from the recording electrode, using single- or multibarrel glass micropipettes. Almost twice as much DA had to be applied in control rat dorsal and ventral striatum to obtain signals comparable to those recorded in the neonatal 6-OHDA-treated animals. In addition, in the dorsal striatum, the later portions of the DA clearance signals were significantly prolonged in the 6-OHDA group. Some clearance decay times in ventral striatum were also significantly prolonged in the neonatal 6-OHDA-treated rats. Concomitant application of the DA uptake inhibitor, nomifensine, in conjunction with the DA ejections, produced signal characteristics in the control striatum that were similar to those seen in the neonatal 6-OHDA-treated striatum. Taken together, these data support the hypothesis that a major component of the clearance of extracellular DA is dependent on intact terminals with high-affinity DA uptake, and that loss of DA afferents from neonatal 6-OHDA treatment results in a slowed clearance time of extracellular DA which is not apparently compensated by the enhanced 5-HT fiber ingrowth.

Animals↗
PubMed1993

Acidic and basic fibroblast growth factor mRNAs are increased in striatum following MPTP-induced dopamine neurofiber lesion: assay by quantitative PCR.

Acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF), the two best characterized members of a growing family of heparin-binding growth factors, have been shown to affect both survival of cultured neurons and regeneration of nerve terminals when applied exogenously. The endogenous expression of these growth factors in response to brain injury is not well understood. We have utilized the Swiss-Webster mouse, treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and a quantitative polymerase chain reaction assay to examine changes in endogenous synthesis of mRNA for both aFGF and bFGF in the striatum and substantia nigra. We have found that MPTP treatment results in a loss of 95% of dopaminergic function and is accompanied by an increase in expression of both aFGF and bFGF in the striatum at 1 week post-lesion. After 5 weeks, the terminals appear to be regenerating and FGF mRNA expression has returned to control levels. These results suggest that cellular reaction to chemical lesion in the brain may involve changes in growth factor expression, including both aFGF and bFGF.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

In vivo electrochemical measurements and electrophysiological studies of rat striatum following neonatal 6-hydroxydopamine treatment.

The effects of neonatal treatment (one day after birth) with the neurotoxin, 6-hydroxydopamine (75 micrograms/10 microliters intracisternal), were studied in the striatum of normal adult and treated Sprague-Dawley rats. Measurements of monoamine levels in the dorsal striatum and nucleus accumbens, by high-performance liquid chromatography coupled with electrochemical detection, showed that neonatal 6-hydroxydopamine treatment produced a permanent and massive destruction of striatal dopamine. The effects were more pronounced in the dorsal striatum than in the nucleus accumbens. In addition, serotonin levels were elevated in the rat striatum as a consequence of the neonatal treatment. Rapid chronoamperometric recordings of K(+)-evoked monoamine overflow using Nafion-coated recording electrodes were investigated in both the dorsal and ventral striatum of control and neonatally lesioned rats. The potassium-evoked responses recorded from the dorsal striatum of the 6-hydroxydopamine-treated rats were significantly reduced in amplitude as compared to controls. In addition, the reduction/oxidation current ratios of the responses were more serotonin-like, in contrast to the dopamine-like current ratios measured in the striatum of untreated animals. In ventral striatum, the amplitudes of the K(+)-evoked responses were not significantly reduced versus control. However, the K(+)-evoked signals were more serotonin-like in their electrochemical characteristics as compared to controls. In addition to the release studies, extracellular single-unit electrophysiological recordings were performed in normal and neonatally 6-hydroxydopamine-treated rats. The spontaneous discharge rate of striatal neurons in the neonatally 6-hydroxydopamine-treated rats was similar to that of control rats. This is in contrast to dopamine lesions in adult animals, where a marked elevation of the discharge rate is observed. Local applications of dopamine and serotonin into the striatum of neonatally 6-hydroxydopamine-treated rats elicited excitations of striatal cells rather than the normal inhibitory effects seen in control animals. Taken together, these data suggest that loss of striatal dopamine terminals at birth leads to both pre- and postsynaptic alterations in monoamine pathways.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Development of monoamine systems after neonatal anoxia in rats.

Neurochemical and morphological effects of neonatal anoxia on monoamine systems were studied after 100% N2 exposure for 25 min at 30 h postnatally (postnatal day 2-P2). At 20 min after anoxia, reductions of tissue levels of cerebellar noradrenaline (NA) and striatal dopamine (DA) and metabolites were seen, while 5-hydroxyindoleacetic acid (5-HIAA) was increased in cortex and cerebellum. At P7, NA increased in cerebellum, while serotonin (5-HT) and 5-HIAA decreased in cortex and cerebellum. At P21, increased hippocampal NA and striatal homovanillic acid (HVA) were found, while striatal 5-HT decreased and 5-HIAA increased in striatum and hippocampus. At P60, striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-HIAA levels were found to be enhanced. No effects were seen on 5-HT, tyrosine hydroxylase, or DARPP-32 immunostaining in cortex, hippocampus, and striatum. Thus, the neonatal anoxia induced both acute and persistent neurochemical abnormalities in monoamine systems that were not accompanied by morphological changes detectable with the methods used. The monoamine alterations found could be critically connected to the behavioral disturbances observed in rats after neonatal anoxia. The findings may also be of relevance to dysfunctions seen in humans after perinatal oxygen deficiency, e.g., the attention deficit hyperactivity disorder syndrome.

Animals↗