6-HYDROXYDOPAMINE Lesions of the Striatum Lead to the Alterations of Dopamine Receptor Mrna in Parkinsonian Rats (original) (raw)
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Molecular brain research, 1991
The effect of dopamine depletion or pharmacological blockade of dopamine receptors on striatal and accumbens dopamine D 2 mRNA and receptor levels was assessed by in situ hybridization histoehemistry and receptor autoradiography. The time course of pharmacological blockade with haloperidol demonstrates a complex mode of regulation of dopamine De mRNA and receptor levels. By day 8 of haloperidol treatment, D 2 mRNA and receptor levels were decreased (up to 20%) in the medial and anterior aspects of the caudate-putamen (mCPU and aCPU) and the nucleus accumbens (NAc). However, by day 21 of haloperidol treatment, D 2 mRNA and receptor were increased relative to vehicle-injected controls. Likewise, unilateral dopamine depletion due to 6-hydroxydopamine (6-OHDA) lesions of mesencephalic dopaminergic neurons resulted in decreased levels of D 2 receptor mRNA by day 8 post-lesion in the ipsilateral mCPU, aCPU and the NAc. However, at days 14 or 21 post-lesion, there was a reversal of the effect with increases of up to 22% in all brain regions ipsilateral to the lesion. Although no decreases in receptor level were observed at day 8, significant increases in receptor level in all three brain regions were detected at days 14 and 21 post-lesion. The results demonstrate that midbrain dopaminergic innervation exerts tonic effects on the levels of dopamine D 2 receptor and mRNA in the caudate-putamen and the nucleus accumbeus of the rat. Changes in receptor level are frequently accompanied by comparable changes in mRNA level, indicating a mass action relationship between receptor level and receptor biosynthesis in these forebrain regions in the rat.
Dopamine Receptor mRNA Expression in Human Striatum and Neocortex
Neuropsychopharmacology, 1996
The distributions of the transcripts encoding the five dopamine receptors have been determined in the human striatum and selected regions of the neocortex. In the striatum significant levels of dopamine receptor expression are restricted to the D1, D2, and 03 receptors. D1 and 02 receptor messenger ribonucleic acids (mRNAs) are homogeneously distributed throughout the caudate, putamen, and nucleus accumbens. 03 receptor mRNA is particularly enriched in the nucleus accumbens, with moderate levels in the ventral putamen. In the prefrontal cortex 01 and D4 receptor mRNAs are the most abundant, although the other three transcripts are seen at lower levels.
Neuroscience, 1995
Previous studies have established that selective damage to the early-developing components of the mesostriatal dopamine system produces profound changes in dopamine D~ receptor-mediated behaviors, while decreasing D t receptor density. In order to better understand the effects of early intrastriatal 6-hydroxydopamine lesions, we studied the ontogenetic expression (postnatal days 7, 14, 35 and 90) of D 1 and D 2 receptors, and their corresponding messenger RNAs, in rats that had received intrastriatal 6-hydroxydopamine or vehicle lesions on postnatal day 1. Using receptor autoradiography, significant (P < 0.05) decreases in [3H]SCH 23390 binding to D~ receptors in the rostral and caudal dorsomedial and ventromedial caudate of 6-hydroxydopamine-lesioned animals were evident by postnatal day 7, and remained depressed at all future time points. A significant decrease in D t receptor concentration occurred in the dorsolateral caudate at later time points (postnatal days 35 and 90).
Molecular Brain Research, 1994
The glutamate analogue kainic acid was injected into the hippocampus of intact or 6-hydroxydopamine deafferented rats to investigate the influence of hippocampal neurons on the expression of dopamine D l and D 2 receptor mRNAs in subregions of the striatal complex and possible modulation by dopaminergic neurons. Quantitative in situ hybridization using 35S-labeled oligonucleotide probes specific for dopamine D~ and D 2 receptor mRNAs, respectively, were used. It was found that an injection of kainic acid into the hippocampal formation had alone no significant effect on dopamine D I or D E receptor mRNA levels in any of the analyzed striatal subreglons In animals analyzed 4 h after the injections. Kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion produced an increase in D 1 receptor mRNA levels in the ipsilateral medial caudate-putamen, and a bilateral increase in core and shell of nucleus accumbens (ventral striatat limbic regions). A unilateral 6-hydroxydopamine lesion alone caused an increase in D 2 receptor mRNA in the lateral caudate-putamen (dorsal striatal motor region) ipsilateral to the lesion and an increase in D l receptor mRNA in the accumbens core ipsilateral to the lesion. However. in dopamine-lesioned animals, dopamine D 1 receptor mRNA levels were increased bilaterally in nucleus accumbens core and shell and in the ipsilateral medial caudate-putamen following kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion These results indicate a differential regulation of the expression of dopamine D l and D 2 receptor mRNAs by midbrain and hippocampal neurons. Dopamine D~ receptor mRNA levels are affected in ventral striatal limbic regions and regulated by a mechanism probably involving both glutamate and dopamine transmission. It appears that hippocampal and dopamine neurons interact in regulating dopamine D~ receptor mRNA levels in the ventral striatum. In contrast, dopamine D E receptor mRNA levels are mainly affected in dorsal striatal motor regions, and only by dopamine deafferentation.
Effect of 6-hydroxydopamine on striatal GDNF and nigral GFRα1 and RET mRNAs in the adult rat
Molecular Brain Research, 2003
Exogenous GDNF as well as vectors containing the gene for this trophic factor has been shown to be neuroprotective in animal models of Parkinson's disease. We therefore investigated whether changes in striatal GDNF protein and nigral mRNA levels of its co-receptors GFRa1 and RET occur in response to lesions of dopamine (DA) neurons and examined the temporal profile of these changes as they relate to the loss of dopaminergic markers. Rats were lesioned with 6-hydroxydopamine and sacrificed 3 h to 60 days post-infusion. DA tissue levels in the striatum and tyrosine hydroxylase immunoreactivity in the substantia nigra (SN) and ventral tegmental area (VTA) were used to determine the size of the lesions. GDNF protein was measured in the striatum using radioimmunocytochemistry. In situ hybridization was used to determine alterations in the mRNAs of RET and GFRa1 in the SN and VTA. We observed no persistent changes in GDNF protein in the striatum in response to 6-hydroxydopamine over the 60-day observation period, suggesting that compensatory changes in this trophic factor do not occur in response to injury. Dramatic decreases in RET and GFRa1 were observed in both SN and VTA that were generally correlated with the loss of TH protein and striatal DA content, strongly suggesting that these receptors are located on DA neurons and that the protective effect of GDNF reflects a direct action of the trophic factor on these neurons.
Molecular Brain Research, 1995
The distribution of the mRNAs encoding the dopamine D1, D2 and D5 receptors was determined in brain tissues obtained from intact female rhesus monkeys, using a ribonuclease protection assay. Tissue blocks from the frontal cortex, striatum, thalamus, hippocampus and substantia nigra were dissected and total RNA was extracted. Dopamine D2 and D5 receptor DNA fragments were generated from rhesus monkey genomic DNA using polymerase chain reaction. To generate dopamine receptor subtype-specific cRNA probes, DNA fragments corresponding to the carboxy terminus of the rhesus monkey D1 and D2 receptor genes and to the putative transmembrane domain regions (IV-VI) of the D5 receptor gene, were subcloned into the pGEM3Z/4Z vectors. Expression of D1 receptor mRNA exhibited significant regional differences: striatum > > > cerebral cortex _> hippocampus > lateral thalamus. D1 receptor mRNA was found in low quantities in the medial thalamus, but was not consistently expressed in the substantia nigra area. In contrast, D2 receptor mRNA was detected in all regions that were studied: striatum > > > substantia nigra > > hippocampus > cerebral cortex >_ medial thalamus >_ lateral thalamus. D5 receptor mRNA was also expressed in all regions, with highest levels in the cerebral cortex, striatum and lateral thalamus, and moderate levels in the substantia nigra, medial thalamus and the hippocampus. The D5 receptor mRNA appears to be widely distributed in the monkey brain. Most interesting is the expression of D5 receptor mRNA in tissues of the substantia nigra area.
Psychiatry and Clinical Neurosciences, 1992
Abstract: In order to investigate whether changes of the two mRNAs encoding the D2 receptor isoforms were induced by chronic haloperidol or methamphetamine treatment in rats, we measured the brain mRNA levels using in situ hybridization histochemistry (ISHH). We used two oligonucleotide probes, an “insert” probe to hybridize with the longer D, receptor, D2(444), mRNA, and a “spanning” probe to hybridize with the shorter D2 receptor, D2(415), mRNA. Both D2 mRNAs were detected by ISHH in the caudate putamen, nucleus accumbens, substantia nigra, pars compacta and ventral tegmental men. The distributions and the amounts of the mRNAs for the two D2 isoforms did not change after chronic administration of haloperidol (1 mg/kg/day for 14 days, ip) or methamphetamine (4 mg/kg/day for 14 days, ip). These results suggest that the changes of D2 receptor density induced by chronic neuroleptic and psychostimulant treatment are not due primarily to receptor expression.
Neuroscience, 2016
l-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson's disease (PD). With prolonged treatment (⩾5years) the majority of patients will develop abnormal involuntary movements as a result of l-DOPA treatment, known as l-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of l-DOPA plus the dopa decarboxylase inhibitor benserazide (4mg/kg and 7.5mg/kgs.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60min after l-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expr...
Molecular Brain Research, 1997
. The present study examined the effects of prolonged L-DOPA treatment 6 months alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the mesostriatal dopaminergic pathway on substance P and enkephalin mRNA expression in the rat neostriatum. This was done by means of quantitative in situ hybridization histochemistry. As reported previously, the unilateral dopaminergic lesion induced a significant and homogeneous decrease in striatal substance P mRNA expression and a marked increase in enkephalin mRNA expression in the ipsilateral neostriatum which was more pronounced in the dorsolateral than ventromedial part of the structure. Long-term L-DOPA treatment alone had no significant effects on the two striatal peptide mRNA levels. The chronic L-DOPA treatment in 6-hydroxydopamine-lesioned rats was found to partially reverse the lesion-induced down-regulation of substance P mRNA expression, without significantly affect the up-regulation of enkephalin when considering the neostriatum as a whole. Topographical analysis revealed that long-term L-DOPA treatment reversed, in fact, both post-lesional enkephalin and substance P responses to 6-hydroxydopamine lesion, in the ventromedial neostriatum, without significantly modified these peptide responses in the dorsolateral neostriatum. These findings provide new evidence that prolonged L-DOPA treatment differentially affects the post-lesional peptide responses in the ventromedial and dorsolateral parts of the neostriatum, suggesting regional cellular mechanisms in the neostriatum underlying the benefit andror side-effects of L-DOPA treatment in parkinsonian patients. q 1997 Elsevier Science B.V.