| 1. |
- Johansson, P. A., et al.
(författare)
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Alterations in cortical and basal ganglia levels of opioid receptor binding in a rat model of L-DOPA-induced dyskinesia
- 2001
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 8:2, s. 220-239
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Tidskriftsartikel (refereegranskat)abstract
- Opioid receptor-binding autoradiography was used as a way to map sites of altered opioid transmission in a rat model of L-DOPA-induced dyskinesia. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathways sustained a 3-week treatment with L-DOPA (6 mg/kg/day, combined with 12 mg/kg/day benserazide), causing about half of them to develop dyskinetic-like movements on the side of the body contralateral to the lesion. Autoradiographic analysis of mu-, delta-, and kappa-opioid binding sites was carried out in the caudate-putamen (CPu), the globus pallidus (GP), the substantia nigra (SN), the primary motor area, and the premotor-cingulate cortex. The dopamine-denervating lesion alone caused an ipsilateral reduction in opioid radioligand binding in the CPu, GP, and SN, but not in the cerebral cortex. Chronic L-DOPA treatment affected opioid receptor binding in both the basal ganglia and the cerebral cortex, producing changes that were both structure- and receptor-type specific, and closely related to the motor response elicited by the treatment. In the basal ganglia, the most clear-cut differences between dyskinetic and nondyskinetic rats pertained to kappa opioid sites. On the lesioned side, both striatal and nigral levels of kappa binding densities were significantly lower in the dyskinetic group, showing a negative correlation with the rats' dyskinesia scores on one hand and with the striatal expression of opioid precursor mRNAs on the other hand. In the cerebral cortex, levels of mu and delta binding site densities were bilaterally elevated in the dyskinetic group, whereas kappa radioligand binding was specifically increased in the nondyskinetic cases and showed a negative correlation with the rats' dyskinesia scores. These data demonstrate that bilateral changes in cortical opioid transmission are closely associated with L-DOPA-induced dyskinesia in the rat. Moreover, the fact that dyskinetic and nondyskinetic animals often show opposite changes in opioid radioligand binding suggests that the motor response to L-DOPA is determined, at least in part, by compensatory adjustments of brain opioid receptors.
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| 2. |
- Cenci, M. A., et al.
(författare)
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Serotonin release from mesencephalic raphe neurons grafted to the 5,7-dihydroxytryptamine-lesioned rat hippocampus : Effects of behavioral activation and stress
- 2000
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 164:2, s. 351-361
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Tidskriftsartikel (refereegranskat)abstract
- Transplants of fetal midbrain raphe neurons into the adult brain have been shown to promote recovery of complex behavioral deficits in several experimental models, but the mechanisms underlying these effects are only partially understood. In the present study, we have used a well-characterized model system to ascertain whether midbrain raphe graft can display behaviorally relevant changes in transmitter release and/or metabolism. Fetal mesencephalic raphe neurons were grafted unilaterally into the hippocampus previously deprived of its innate serotonergic innervation by intraventricular injections of 5,7-dihydroxytryptamine. The contralateral hippocampus remained as a non-grafted, lesioned control. Microdialysis probes were implanted in the hippocampus 5-7 months postgrafting. Under baseline conditions, extracellular levels of serotonin were similar to normal in the grafted hippocampi, but undetectable on the contralateral, non-grafted side. Levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were markedly higher than normal in the grafted hippocampi, but dramatically reduced on the contralateral nongrafted side. Handling stimulation (gentle stroking of a rat's fur and tail for 15 min) induced a 64% increase in serotonin output in the intact rats and a small but significant 12% increase in the grafted animals. Non-noxious tail-pinch (15 min) enhanced serotonin release by 86% in the intact rats and 28% in the grafted ones. Extracellular 5-HIAA levels remained unchanged during both handling and tail-pinch in both the intact and the grafted rats. Forced immobilization of the rats for 15 min induced a transient 124% increase in extracellular serotonin levels in the intact rats and a significant 19% increase in the grafted animals, whereas swimming in temperate water (25-30°C; 15 min) induced no detectable changes in serotonin output in any of the groups. 5-HIAA levels remained unchanged during forced immobilization, but were significantly reduced during the swimming session in both the intact (-38%) and grafted (-15%) animals. The present results indicate that median raphe grafts can become functionally integrated in the denervated host hippocampus and respond by altered indole output when the animal is exposed to different types of environmental challenges.
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| 3. |
- Winkler, Christian, et al.
(författare)
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Regulation of neuropeptide mRNA expression in the basal ganglia by intrastriatal and intranigral transplants in the rat Parkinson model.
- 2003
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Ingår i: Neuroscience. - 1873-7544. ; 118:4, s. 1063-1077
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that intrastriatal transplants of dopamine (DA)-rich fetal ventral mesencephalic (VM) tissue can correct denervation-induced changes in the cellular expression of neuropeptide and receptor mRNAs in the rat Parkinson model. However, with the standard transplantation approach normalization of all cellular parameters has not been obtained. This may be due either to the incomplete striatal reinnervation achieved by these transplants, or to the ectopic placement of the grafts. In the present study we have used a microtransplantation approach to obtain a more complete reinnervation of the denervated striatum (20 micrograft deposits spread over the entire structure). Neurons were also implanted directly into the substantia nigra. In rats with multiple intrastriatal VM transplants the lesion-induced upregulation of mRNAs encoding for preproenkephalin (PPE), the D2-type DA-receptor, and the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) was normalized throughout the striatum, whereas the lesion-induced downregulation of preprotachykinin mRNA was unaffected. Intranigral grafts of either fetal DA-rich VM tissue or GABA-rich striatal tissue did not induce any changes in striatal neuropeptide and D2-receptor mRNA expression despite significant behavioral improvement. Comparison of the behavioral data with levels of neuropeptide expression showed that in rats with intrastriatal VM transplants a complete normalization of striatal PPE and GAD67 mRNA expression did not translate into a complete recovery of spontaneous motor behaviors. The results show that extensive DA reinnervation of the host striatum by multiple VM microtransplants is insufficient to obtain full recovery of all lesion-induced changes at both the cellular and the behavioral level. A full reconstruction of the nigrostriatal pathway or, alternatively, modulation of basal ganglia function by grafting in non-striatal regions may be required to further improve the functional outcome in the DA-denervated brain.
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