Mechanisms of excitation and inhibition in the nigrostriatal system

The extracellular responses of neurones in the neostriatum following single pulse stimulation of the substantia nigra were investigated in urethane anaesthetized rats. Low intensity stimulation (less than 10 V) evoked single large amplitude spikes while higher intensities (10-20 V) elicit a high frequency burst of small amplitude spikes or waves. When spontaneous or glutamate-induced large spikes are recorded, nigral stimulation causes their inhibition coincidentally with the development of a burst. If the burst is prevented, the inhibitory response disappears. Both the nigral evoked inhibition and burst response are unaffected by iontophoretically or systemically administered antonists of dopamine or by chemical lesions of the dopamine-containing nigral neurones. The monosynaptic activation of large amplitude striatal neurones, which could also be identified antidromically by stimulation of the globus pallidus, was reversibly blocked by dopamine antagonists. It is concluded (a) that the burst responses are induced through the antidromic excitation of striatonigral axons within the striatum; (b) that the striatal neurones thus activated are inhibitory interneurones and (c) that the dopamine-containing neurones of the nigra make excitatory synaptic contact with a population of striatal output cells, some of which at least project to the globus pallidus.     

Some carbohydrates found in pollen and pollen substitutes are toxic to honey bees

Carbohydrates in some pollen substitutes (galactose, lactose, raffinose, stachyose, glucuronic acid, galacturonic acid, polygalacturonic acid, and pectin) were toxic to caged adult Apis mellifera L. These toxins can be diluted to safe levels by sucrose. Collected nectar apparently dilutes the toxic sugars in pollen thus permitting assimilation of essential nutrients from pollen.     

Deprenyl induces GFAP immunoreactivity in the intact and injured dopaminergic nigrostriatal system but fails to counteract axotomy-induced degenerative changes

There is increasing evidence of a trophic-like mechanism for some effects ascribed to deprenyl therapy in the central nervous system. For that, we studied the effect of chronic treatment with deprenyl in an animal model of Parkinson's disease induced by unilateral knife transection of the medial forebrain bundle (MFB) in adult rats. The experimental conditions included a 3-week pretreatment with deprenyl before stereotaxic transection of the MFB. Following surgery, deprenyl treatment was maintained for 3 weeks. Neurochemical and immunohistochemical procedures were used to study the dopaminergic system and reactive astrocytes in the nigrostriatal system. Deprenyl treatment failed to counteract the axotomy-induced degenerative changes of the nigrostriatal dopaminergic system. However, it was effective in increasing the density of reactive astrocytes in terms of glial fibrillary acidic protein (GFAP) immunoreactivity in the intact contralateral substantia nigra and also in further enhancing the axotomy-induced increase of GFAP immunolabeled astrocytes in the lesioned substantia nigra. This deprenyl-induced effect on GFAP immunoreactivity was confined to substantia nigra without effect in striatum. In addition, we found a medial to lateral gradient decrease in the distribution pattern of GFAP immunolabeled astrocytes. Axotomy increased the number of reactive astrocytes in either striatal area examined, but yet the preferential distribution pattern of reactive astrocytes in striatum was still evident.     

Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system

The pathogenesis of Parkinson's disease is still poorly understood. To address the hypothesis that immune-mediated events, such as microglial activation, may be involved in the dopaminergic neurodegeneration, we have studied the effect that intranigral injection of the immunostimulant lipopolysaccharide has on monoaminergic neurotransmitters in rats. Activation of microglial cells, visualized by immunohistochemistry with a specific monoclonal antibody, was already obvious 2 days after injection. In relation to the biochemical parameters studied, we found a significant decrease of dopamine levels in both the substantia nigra and striatum up to at least 21 days after intranigral injection of lipopolysaccharide. This result was supported by the decrease in tyrosine hydroxylase activity and the loss of tyrosine hydroxylase-positive neuronal bodies, shown by immunohistochemistry. These alterations of the dopaminergic system did not reverse during the interval studied (21 days); conversely, the serotoninergic system suffered only transient damage. In addition, we found that the neurotoxic effect of lipopolysaccharide was not mediated by nitric oxide. Based on our results we suggest that the nigrostriatal dopaminergic system is susceptible to damage by inflammatory events and that these may be implicated in neurodegeneration processes such as Parkinson's disease.     

Melatonin protects 6-OHDA-induced neuronal death of nigrostriatal dopaminergic system

In vivo neuroprotective effects of melatonin on the nigrostriatal dopaminergic system in rats unilateral 6-hydroxydopamine (6-OHDA) lesions were tested. Two weeks after lesioning the dopamine receptor agonist, apomorphine produced rotational asymmetry. In contrast, melatonin treatment significantly reduced the motor deficit following apomorphine challenge. Analysis by tyrosine hydroxylase (TH) immunocytochemistry revealed the loss of cell bodies in the substantia nigra (SN) and absence of terminals in the dorsolateral striatum ipsilaterally. Melatonin treatment also resulted in the survival of dopaminergic neurons in SN and TH-immuoreactive terminals in the dorsolateral striatum. These behavioral and histochemical results may indicate a neuroprotective action of melatonin and suggest a potential pharmacological role in the treatment of Parkinson's disease.     

GDNF administration induces recovery of the nigrostriatal dopaminergic system both in young and aged parkinsonian mice

Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor beta superfamily and acts as a neurotrophic factor for the nigrostriatal dopaminergic system. GDNF was injected stereotaxically into the striatum of young (2 months old) and aged (12 months old) C57BL/6 mice that were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 1 week earlier. Immunocytochemical and neurochemical analyses showed significant recovery of the nigrostriatal dopaminergic system both in young and in aged mice. Since Parkinson's disease is a neurodegenerative disorder mainly affecting elderly people, this result demonstrates the potential usefulness of GDNF in treating Parkinson's disease.     

Carboplatin toxic effects on the peripheral nervous system of the rat

OBJECTIVE: Few studies have investigated perceptions of operant conditioning programs by anorexic patients. This study examined patients' perceptions of the Bed Rest (BR) component which is employed in some operant conditioning programs. METHODS: A sample of 48 anorexic inpatients was administered a survey to elicit their attitudes towards BR. RESULTS: Results from the survey suggested that most patients perceived BR in a negative way. The main complaint, however, was not punishment or humiliation, as predicted, but isolation and boredom. A number of patients concluded that they wanted more individualization and distraction and less restriction while on BR. DISCUSSION: The findings justify the use of BR within a humane framework in the inpatient treatment of anorexia nervosa, but suggest that patients' perceptions of BR warrant systematic scrutiny.     

Specificity of avoidance deficits produced by 6-hydroxydopamine lesions of the nigrostriatal system of the rat.

Three experiments with a total of 65 male Wistar rats showed that microinjections of 6-hydroxydopamine (6-OHDA) into the dopaminergic nigrostriatal system (NS) impaired acquisition of a 2-way avoidance response. This effect was independent of nutritional deficiencies since it was observed even when a special postoperative treatment ensured a comparable state of nutrition in control and experimental Ss. It was likewise independent of locomotor disturbances. Because doses of 6-OHDA that impaired acquisition of an active avoidance response produced lesions that were, to a great extent, nonspecific, behavioral effects of these doses cannot be entirely ascribed to selective destruction of the NS. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurotoxic effects of papaverine, tetrahydropapaverine and dimethoxyphenylethylamine on dopaminergic neurons in ventral mesencephalic-striatal co-culture

We report neurotoxic effects of papaverine, tetrahydropapaverine, dimethoxyphenylethylamine (DMPEA), and 1-methyl-4-phenylpyridinium ion (MPP+) on dopaminergic neurons in ventral mesencephalic-striatal co-culture. These compounds have been reported as mitochondrial toxins which may be implicated in the etiology and pathogenesis of Parkinson's disease. Tyrosine hydroxylase (TH)-positive neurons were decreased in dose-dependent manner by these compounds. Papaverine and MPP+ were most toxic to TH-positive neurons among the compounds tested. The order of the toxicity on TH-positive neurons was papaverine, MPP+, tetrahydropapaverine and then DMPEA. This order of toxicity was approximately the same as that reported on the inhibitory effect of these compounds on NADH-linked mitochondrial respiration and complex I activity. These findings indicate that the presence of dimethoxy residues in the catechol ring augments toxicity to dopaminergic neurons in culture.     

Effects of testosterone upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system of C57/B1 mice

We have recently reported that treatment of gonadectomized female and male C57/B1 mice with the gonadal steroid hormone, estrogen, reduced nigrostriatal dopaminergic neurotoxicity resulting from the Parkinson's-like inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the present report we examined whether the predominantly male gonadal steroid hormone, testosterone, would similarly modulate MPTP-induced neurotoxicity. Male C57/B1 mice were assigned to one of the following five treatment conditions: (1) Intact, (2) Orchidectomized, (3) Intact + MPTP, (4) Orchidectomized + Testosterone + MPTP and (5) Orchidectomized + MPTP. Corpus striatal and olfactory tubercle dopamine. DOPAC and norepinephrine concentrations were determined from the animals within each of the five treatment conditions. Orchidectomy alone failed to alter striatal dopamine and DOPAC concentrations, with levels obtained being similar to that of Intact animals. MPTP treatment significantly reduced striatal reduced striatal dopamine and DOPAC concentrations, regardless of hormonal condition of the animal. Similar results were obtained for olfactory tubercle determinations, with the exception that DOPAC levels from Orchidectomized mice were significantly greater than Intact males. No significant differences were obtained for norepinephrine within either brain area sampled. These results show that unlike estrogen, testosterone is devoid of any capacity to modulate nigrostriatal dopaminergic neurotoxicity resulting from MPTP. These findings may be related to the gender differences which exist in the prevalence of Parkinson's disease.     

Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme

A new classification, based on the pattern and distribution of cutaneous lesions, separates erythema multiforme major from Stevens-Johnson syndrome. A retrospective re-classification of 76 cases supported the validity of that separation by demonstrating differing causes and pathology. Another prospective international case-control study found differing demographic characteristics and risk factors between erythema multiforme major on the one hand and Stevens-Johnson syndrome or toxic epidermal necrolysis on the other. Erythema multiforme major was mainly related to Herpes virus infection, while Stevens-Johnson syndrome and toxic epidermal necrolysis were associated with drug reactions.     

Synaptology of the nigrostriatal projection in relation to the compartmental organization of the neostriatum in the rat

The patch-matrix organization of the striatal complex, which is fundamental to the structural and functional organization of the basal ganglia, is characterized on the basis of both connections and neurochemistry. In order to determine whether differences in the connections and neurochemistry are reflected in differences in synaptic organization, we examined the synaptology of the dopaminergic nigrostriatal projection in the patch-matrix complex of the rat. Three approaches were used. First, deposits of the anterograde tracer, biotinylated dextran amine, were placed in the substantia nigra. Sections of perfuse-fixed neostriatum were then processed to reveal anterogradely-labelled nigrostriatal axons and calbindin-D28k immunoreactivity, a marker for the patch-matrix complex. Secondly, sections of perfuse-fixed neostriatum were immunolabelled to reveal both tyrosine hydroxylase, a marker for dopaminergic structures and calbindin-D28k. Labelled axons in the patches and the matrix were examined at both the light and the electron microscopic levels. Finally, in order to test for the presence of fixed GABA in sub-type of anterogradely-labelled terminals in the neostriatum, ultrathin sections were immunolabelled by the post-embedding immunogold method. Based on morphological analysis, anterogradely-labelled nigrostriatal axons were divided into two types (Type I and Type II). The density of tyrosine hydroxylase labelling in the neostriatum prevented the classification of immunolabelled nigrostriatal axons. The Type I anterogradely-labelled axons and tyrosine hydroxylase-positive axons were found both in the patches and in the matrix. They both formed symmetrical synapses with spines, dendrites and occasionally somata. The morphology, dimensions, type of synaptic specialization and the distribution of postsynaptic targets of axons labelled by both methods were similar in the patches and the matrix. The Type I anterogradely-labelled axons were immunonegative for GABA. The Type II anterogradely-labelled axons were GABA-immunopositive, were found only in the matrix and were only present in those animals in which retrograde labelling was observed in the globus pallidus, they are thus not part of the dopaminergic nigrostriatal projection. It is concluded that although the patch-directed and matrix-directed dopaminergic projections from the ventral mesencephalon arise from different populations of dopaminergic neurons, their innervation of neurons in the patches and matrix is similar. The anatomical substrate, and therefore probably also the mechanism, for dopaminergic modulation of the flow of cortical information through the striatal complex in essentially the same in the patch and in the matrix sub-divisions of the striatal complex.     

Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat

Partial lesions of the nigrostriatal dopamine system have been investigated with respect to their ability to induce consistent long-lasting deficits in movement initiation and skilled forelimb use. In eight different lesion groups 6-hydroxydopamine (6-OHDA) was injected at one, two, three, or four sites into the lateral sector of the right striatum, in a total dose of 20-30 microgram. Impairments in movement initiation in a forelimb stepping test, and in skilled paw use in a paw-reaching test, was seen only in animals where the severity of the lesion exceeded a critical threshold, which was different for the different tests used: single (1 x 20 microgram) or two-site (2 x 10 microgram) injections into the striatum had only small affects on forelimb stepping, no effect on skilled paw use. More pronounced deficits were obtained in animals where the same total dose of 6-OHDA was distributed over three or four sites along the rostro-caudal extent of the lateral striatum or where the injections were made close to the junction of the globus pallidus. The results show that a 60-70% reduction in tyrosine hydroxylase (TH)-positive fiber density in the lateral striatum, accompanied by a 50-60% reduction in TH-positive cells in substantia nigra (SN), is sufficient for the induction of significant impairment in initiation of stepping. Impaired skilled paw-use, on the other hand, was obtained only with a four-site (4 x 7 microgram) lesion, which induced 80-95% reduction in TH fiber density throughout the rostrocaudal extent of the lateral striatum and a 75% loss of TH-positive neurons in SN. Drug-induced rotation, by contrast, was observed also in animals with more restricted presymptomatic lesions. The results indicate that the four-site intrastriatal 6-OHDA lesion may be a relevant model of the neuropathology seen in parkinsonian patients in a manifest symptomatic stage of the disease and may be particularly useful experimentally since it leaves a significant portion of the nigrostriatal projection intact which can serve as a substrate for regeneration and functional recovery in response to growth promoting and neuroprotective agents.     

Quantitative behavioral study of the acute and long-term effects of two-stage bilateral 6-OHDA-induced lesions of the nigrostriatal dopaminergic system in monkeys.

Bilateral lesions of the nigrostriatal dopaminergic system (2-stage lesions separated by 5–6 months) were induced in 3 monkeys trained to initiate forelimb-reaching movements toward a visual target. After each lesion, analysis of the task performance over several months of regular testing showed that the latency to initiate the movement was permanently prolonged in monkeys showing 90% or more striatal dopamine depletion, whereas animals with less severe depletion completely recovered the task performance. Several months after a unilateral nigrostriatal damage, a lesion on the other side produced impairments only on the side of the body contralateral to that second lesion and did not reinstate the deficits on the side previously affected by the first lesion. This suggests that the remaining intact nigrostriatal dopaminergic system may not be involved in the long-term behavioral recovery observed in monkeys with a unilateral lesion. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genome-linked toxic responses to dietary iron overload

Genome-related differences to Fe overload between and within rodent species were evaluated in the present study. Male B6C3F1 mice, yellow and black C5YSF1 mice, and Fischer 344 (F344) rats were fed AIN-76A diets containing 35 (control), 1,500, 3,500, 5,000, or 10,000 micrograms carbonyl Fe/g for 12 wk. No effects on body weight gain were observed in the B6C3F1 and black C5YSF1 mice, whereas at all doses of Fe above the control, weight gain was reduced in yellow C5YSF1 mice and F344 rats. At the 10,000 micrograms Fe/g dose, 9 of 12 rats died, but there was no mortality among the mice. In all animals, there was a dose-related increase in liver nonheme Fe, and the Fe was stored in hepatocytes predominantly in the periportal region. There was significant hypertrophy of the hepatocytes in both B6C3F1 mice and F344 rats fed the 10,000 micrograms Fe/g diet. PCNA assays showed significant stimulatory effects of the high dose of Fe on hepatocyte proliferation in the F344 rats and the C5YSF1 mice but not in the B6C3F1 mice. In the rat, there was pancreatic atrophy with loss of both endocrine and exocrine tissue. Morphometric evaluation of pancreas showed fewer beta cells in B6C3F1 and yellow C5YSF1 mice but not in the black C5YSF1 mice. There were fewer islets in the yellow C5YSF1 mice, and total and mean islet areas were smaller than in the control mice. Rats in the 10,000 micrograms Fe/g dose group had markedly exacerbated dose-dependent nephropathy and changes in glomerular and tubular epithelium associated with Fe accumulation. The rats also showed degeneration of the germinal epithelium of the testis, formation of multinucleated giant cells, and lack of mature sperm.     

Evaluation of exposure to toxic factors occurring in the cellulose and paper industry

The study covered the work environment of a big plant producing sulfate cellulose, paper and paperboard. Measurements of chemical substance concentrations, performed by a local plant laboratory during the years 1976-1991, were analysed with reference to production departments and particular workplaces. Out of 37 substances under study, 16 were found in the air of workplaces. Their concentrations exceeded periodically hygienic standards. The most frequent excess of TLV applied to such compounds as wood dust (including hard beechwood), non-organic dusts containing 2-50% of crystalline silica and below 2% of silica, welding fumes, furfuryl aldehyde, sulfur dioxide, phenol and hydrogen sulfide. A computer-aided registrer of hygienic data facilitated the follow-up of dynamics of exposure to toxic compounds of workers employed at given workplaces.     

The Bov-B lines found in Vipera ammodytes toxic PLA2 genes are widespread in snake genomes

In the fourth intron of two toxic Vipera ammodytes PLA2 genes a Ruminantia specific 5'-truncated Bov-B LINE element was identified. Southern blot analysis of Bov-B LINE distribution in vertebrates shows that, apart from the Ruminantia, it is limited to Viperidae snakes (V. ammodytes, Vipera palaestinae, Echis coloratus, Bothrops alternatus, Trimeresurus flavoviridis and Trimeresurus gramineus). The copy number of the 3' end of Bov-B LINE in the V. ammodytes genome is between 62,000 and 75,000. At orthologous positions in other snake PLA2 genes the Bov-B LINE element is absent, indicating that its retrotransposition in the V. ammodytes PLA2 gene locus has occurred quite recently, about 5 Myr ago. The amplification of Bov-B LINEs in snakes may have occurred before the divergence of the Viperinae and Crotalinae subfamilies. Due to its wide distribution in Viperidae snakes it should be a valuable phylogenetic marker. The neighbour-joining phylogenetic tree shows two clusters of truncated Bov-B LINE, a Bovidae and a snake cluster, indicating an early horizontal transfer of this transposable element.     

Alterations in intralaminar and motor thalamic physiology following nigrostriatal dopamine depletion

Methoxyacetaldehyde (MALD), a metabolite of 2-methoxyethanol, has been shown to be clastogenic and mutagenic in CHO-AS52 cells. PCR-based-deletion screening of MALD induced CHO-AS52 mutants indicates that MALD induces large deletion mutation. Since MALD has an aldehyde as its reactive functional group, it can react with aldehyde oxidase to produce superoxide. The generation of these reactive oxygen species (superoxide, hydrogen peroxide and hydroxyl radical) may be the mechanism for genotoxicity of MALD. In the present study, TEMPOL and catalase which are ROS modulators were used to study the effects on MALD-induced chromosome damage in CHO-AS52 cells. The results showed that neither TEMPOL nor catalase can protect cells from MALD-induced chromosome aberrations. Therefore, the generation of reactive oxygen species may not be the primary mechanism of action of MALD.