Alterations of nocturnal activity in rats following subchronic oral administration of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline

1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) is neurotoxic when administered to the brain and alters motor behaviour following intraperitoneal administration. We have assessed the long-term effects of oral TaClo administration on nocturnal motor behaviour in rats. Two groups of rats received TaClo orally at a dose of either 0.2 or 0.4 mg/kg twice daily for 7 weeks. The control group was given saline. No change in locomotor activity was observed 4–9 days after the end of the 7-week administration of TaClo. In addition, the spontaneous motor activity was altered dose-dependently 9 months after oral TaClo administration, with an increase in the low-dose TaClo group and a decrease in the high-dose group. Oral administration of TaClo in rats may be useful in investigating the hypothesis that in Parkinson’s disease, an unknown pathogenic factor crossing the intestinal mucosa barrier can induce neurodegenerative processes eventually affecting the entire brain

Lesion of the Cerebellar Noradrenergic Innervation Enhances the Harmaline-Induced Tremor in Rats

Abnormal synchronous activation of the glutamatergic olivo-cerebellar pathway has been suggested to be crucial for the harmaline-induced tremor. The cerebellum receives two catecholaminergic pathways: the dopaminergic pathway arising from the ventral tegmental area/substantia nigra pars compacta, and the noradrenergic one from the locus coeruleus. The aim of the present study was to examine a contribution of the cerebellar catecholaminergic innervations to the harmaline-induced tremor in rats. Rats were injected bilaterally into the cerebellar vermis with 6-hydroxydopamine (6-OHDA; 8 μg/0.5 μl) either alone or this treatment was preceded (30 min earlier) by desipramine (15 mg/kg ip). Harmaline was administered to animals in doses of 7.5 or 15 mg/kg ip. Tremor of forelimbs was measured as a number of episodes during a 90-min observation. Rats were killed by decapitation 30 or 120 min after harmaline treatment. The levels of dopamine, noradrenaline, serotonin, and their metabolites were measured by HPLC in the cerebellum, substantia nigra, caudate–putamen, and frontal cortex. 6-OHDA injected alone enhanced the harmaline-induced tremor. Furthermore, it decreased the noradrenaline level by ca. 40–80% in the cerebellum and increased the levels of serotonin and 5-HIAA in the caudate–putamen and frontal cortex in untreated and/or harmaline-treated animals. When 6-OHDA treatment was preceded by desipramine, it decreased dopaminergic transmission in some regions of the cerebellum while inducing its compensatory activation in others. The latter lesion did not markedly influence the tremor induced by harmaline. The present study indicates that noradrenergic innervation of the cerebellum interacts with cerebral serotonergic systems and plays an inhibitory role in the harmaline-induced tremor

Targeted treatments for fragile X syndrome

Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD. Autistic features are present in a very high percent of individuals with FXS, even those who do not meet full criteria for ASD. Recent major advances have been made in the understanding of the neurobiology and functions of FMRP, the FMR1 (fragile X mental retardation 1) gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to the dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to the dysregulated translational pathway. These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model at multiple stages of development. Clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess cognitive change that might be associated with treatment. Genes known to be causes of ASD interact with the translational pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD. Therefore, targeted treatments developed for FXS may also target subgroups of ASD, and clinical trials in FXS may serve as a model for the development of clinical trial strategies for ASD and other cognitive disorders

Partial loss of dopaminergic neurons in the substantia nigra, ventrotegmental area and the retrorubral area - model of the early beginning of Parkinson's symptomatology?

To test substances which might have protective effects on the dopaminergic system it is necessary to use models with a pathological symptomatology of the early beginning, i.e. models in which the chance exists to arrest the otherwise progressive pathological processes (see Heim et al., 2001). 6- hydroxydopamine (6-OHDA) injected unilaterally into the ventrolateral striatum of rats (6 mug dissolved in 2 mul 0.2% ascorbic acid) leads to specific stereotyped movements after subcutaneous injection of apomorphine both 3 and 13 weeks after surgery. Ten weeks after surgery decreased spontaneous motor activity could be observed. Twelve weeks after 6- hydroxydopamine injection, the animals had difficulties in performing a spatial navigation task when the submerged escape platform was moved to another position. The switching of motor programs was less pronounced. The application of tyrosine- hydroxylase-staining showed a loss of ipsilateral neurones of the substantia nigra compacta as well as of dendrites in the pars reticulata, neurones in the ventral tegmental area and in the retrorubral area ipsilaterally as well as a loss of dopaminergic fibres both ipsilaterally and contralaterally in the striatum which should belong to the contralateral acting substantia nigra afferents. The loss of the neurones and the afferents was induced by the retrograde denervation following the 6-OHDA injection within the ventrolateral striatum. The question arises whether the model used here with the partially loss of dopaminergic neurons and fibres reflects some of pathological symptoms of Parkinson's disease in the early states

Cerebral oligemia and iron influence in cerebral structures - element of Morbus Parkinson models?

The consequences of short phases of restricted cerebral blood flow and iron enrichment of striatal tissues resulted in an animal model that could correspond to the basic features of a model for Parkinson's disease. An automatic and computerized hole-board offers simultaneous data on learning and cognitive (memory capabilities, learning of distinct patterns of distributed food pellets found and eaten in a given time, switches between different locations of food in the holes and in different layout patterns. Wistar rats after 60 min of bilateral clamping of the carotid arteries (BCCA) under pentobarbital anesthesia received 1.5 mu g FeCl3 injected one week after BCCA unilaterally into the ventrolateral striatum. The experiments showed that reduced cerebral Hood flow and increased iron within the striatal tissue had the effect of retard.ng reactions. Rats after BCCA and iron need 180 s to find pellets deep inside holes that are distributed in a distinct pattern. During only 60 or 30s BCCA plus iron rats are no longer able to find the same number of pellets as over 180s. Rats after BCCA plus NaCl do not show such reduced success. These results point to the idea that cerebral oligemia and increased iron in :he striatum stimulate the pathological symptoms of Parkinson's disease which need also more time to have reaction and success (see Fig. 5). The data covering abbreviated time-spans show how heavily the BCCA + Fe animals are dependent on longer times

Neurotoxine und Neuroprotektion: Bedeutung radikalischer Mechanismen und der Atmungsketteninhibition fuer die Aetiologie des Parkinsonsyndroms, der Neurodegeneration und des Alterungsprozesses Schlussbericht

There are no animal models for the investigation of the causes and progression of neurodegenerative diseases - such as Parkinson's Disease -suitable for searching out the pathological mechanisms which may elicit and maintain a progressive disease process. Up till now only a few of the factors that might contribute to the multiactorial pathogenesis of Parkinson's Disease have been established. A large-scale depolyment of non-human primates could not be considered. Rats, subjected to oxidative stress, exhibit a gradually developing assortment of pathological symptoms which strikingly involve the mediation of the dopaminergic system. The pathological symptoms are susceptible to therapeutic interventions. The animals undergo various stages of a set of pathological symptoms which manifests itself among others in a reluctance to undertake changes of rapid motor strategies. They exhibit a diminished ability to learn and to pay attention. Brain regions where such lesions may be elicited are highly specific. At an advanced age, the consequency of oxidative stress show a loss of the D1 mRNA in the dorsal statum without concomitant cell loss. (orig.)Available from TIB Hannover: F99B1195 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung und Forschung (BMBF), Bonn (Germany)DEGerman