Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic neuroleptic treatment in rat produces vacuous chewing movements (VCMs), analogous to TD in humans. We hypothesized that these hyperkinetic movements were due to alterations in striatonigral and striatopallidal GABAergic spiny II neurons. Rats were treated for 36 weeks with haloperidol decanoate and withdrawn for 28 weeks. Striatonigral and striatopallidal neurons were assessed using in situ hybridization histochemistry for mRNA levels of D1 and D2 dopamine receptors, preproenkephalin (ENK), prodynorphin (DYN), protachykinin (substance P), and glutamate decarboxylase (GAD67) in the dorsolateral and ventromedial striatum as well as the nucleus accumbens. Rats that did not develop VCMs (-VCM) had increased D2 receptor and DYN mRNA, and reduced substance P mRNA in the dorsolateral striatum. Rats with persistent VCMs (+VCM) had increased D2 receptor, ENK, and DYN mRNA in both striatal regions, and increased ENK and DYN mRNA in the nucleus accumbens, compared with controls. Relative to -VCM rats, however, +VCM rats only had increased ENK mRNA in the nucleus accumbens. Considering the overall pattern of mRNA changes, the data suggest that alterations in both the D1-mediated striatonigral and the D2-mediated striatopallidal pathways play a role in the expression of the VCM syndrome. To the extent that gene expression parallels changes in neuronal activity, this implies that the VCM syndrome is associated with increased activity in both pathways.
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PMID:Alterations in mRNA levels of D2 receptors and neuropeptides in striatonigral and striatopallidal neurons of rats with neuroleptic-induced dyskinesias. 753 73

GABAergic modulation of enkephalin, substance P and glutamic acid decarboxylase (GAD67) gene expression and the alterations induced by dopamine receptor blockade were studied in the rat striatum. Following subchronic treatment with the GABA-A agonist muscimol, the GABA-B agonist baclofen or the GABA transaminase inhibitor gamma-vinyl GABA there were no significant changes in striatal peptide and GAD67 gene expression. Following repeated administration of the D-2 antagonists, eticlopride and haloperidol, there was an increase in enkephalin and GAD67 mRNA levels and parallel decrease in that of substance P. These were unaffected by co-administration of gamma-vinyl GABA. The D-1 antagonist, SCH 23390 administered alone or together with gamma-vinyl GABA did not alter peptide or GAD67 mRNA levels. It seems that pharmacological stimulation of GABA receptors has little effect on enkephalin, substance P or GAD67 mRNA expression in striatal output neurons.
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PMID:GABAergic modulation of striatal peptide expression in rats and the alterations induced by dopamine antagonist treatment. 753 10

NMDA receptors are composed of proteins from two families: NMDAR1, which are required for channel activity, and NMDAR2, which modulate properties of the channels. The mRNA encoding the NMDAR2D subunit has a highly restricted pattern of expression: in the forebrain, it is found in only a small subset of cortical, neostriatal and hippocampal neurons. We have used a quantitative double-label in situ hybridization method to examine the expression of NMDAR2D mRNA in neurochemically defined populations of neurons. In the neostriatum, NMDAR2D was expressed by the interneuron populations marked by preprosomatostatin (SOM), the 67-kDa form of glutamic acid decarboxylase (GAD67), parvalbumin (PARV), and choline acetyltransferase (ChAT) mRNAs but not by the projection neurons expressing beta-preprotachykinin (SP) or preproenkephalin (ENK) mRNAs. In the neocortex, NMDAR2D expression was observed in only a small number of neurons, but these included almost all of the SOM-, GAD67-, and PARV-expressing interneurons. In the hippocampus, NMDAR2D was not present in pyramidal or granule cells, but was abundant in SOM-, GAD67-, and PARV-positive interneurons. NMDAR2D expression appears to be a property shared by interneurons in several regions of the brain. The unique electrophysiological characteristics conveyed by this subunit, which include resistance to blockade by magnesium ion and long channel offset latencies, may be important for the integrative functions of these neurons. NMDAR2D-containing receptor complexes may prove to be important therapeutic targets in human disorders of movement. In addition, the presence of NMDAR2D subunits may contribute to the differential vulnerability of interneurons to excitotoxic injury.
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PMID:Expression of NMDAR2D glutamate receptor subunit mRNA in neurochemically identified interneurons in the rat neostriatum, neocortex and hippocampus. 891 84

Supranigral infusions of the TrkB-receptor-preferring neurotrophins BDNF or NT-4/5 augment locomotor behaviours, pars compacta firing rates and striatal dopamine metabolism. However these actions of BDNF or NT-4/5 may involve other neurotransmitter systems in addition to dopamine neurons in the substantia nigra. We thus investigated the effects of 2-week supranigral infusions of BDNF or NT-4/5 on rat peptidergic striatonigral neurons and nigral GABAergic neurons. Radioimmunoassay revealed that BDNF and NT-4/5 elevated substantia nigra levels of substance P (by 46 and 57% respectively) and substance K (by 64 and 81%). In addition, BDNF elevated substance K by 59% in a nigral projection area, the superior colliculus. NT-4/5 elevated dynorphin A in the substantia nigra (by 52%) and met-enkephalin in substantia nigra and globus pallidus (by 89%). None of these neuropeptides were altered in the striatum. Consistent with these findings, supranigral infusions of BDNF elevated the mRNA for preprotachykinin A in striatal neurons. In the same animals, glutamic acid decarboxylase (GAD)67 mRNA was increased by 48% in the substantia nigra. The cross-sectional area of GAD67-positive neuronal somata in the BDNF-infused nigra was increased by 59%, and 70% of nigral GABAergic neurons had a cross-sectional area > 550 microns2, whereas 95% of the neurons in vehicle-infused animals had cross-sectional areas < 550 microns2. Thus, supranigral infusions of BDNF or NT-4/5 increase tachykinin mRNA and protein levels within striatonigral neurons and increase the size and GAD67 mRNA expression levels of nigral GABAergic neurons. These results suggest that BDNF or NT-4/5 may modify the output of the basal ganglia not only through effects on dopamine neurons but also by increasing neurotransmission in striatonigral peptidergic and nigral GABAergic pathways.
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PMID:Effects of BDNF and NT-4/5 on striatonigral neuropeptides or nigral GABA neurons in vivo. 892 Dec 61

In the striatum, interneurons have not been as well characterized physiologically as the spiny projection cells. We found that the neostriatal interneurons can be divided at least into three classes by physiological, chemical and morphological criteria. The first was FS cells (fast-spiking cells) which fired very short-duration action potentials at constant spike frequency during depolarizing pulses, were immunoreactive for parvalbumin (calcium-binding protein), and had axons with very dense collateralization within or near their dendritic fields. Another class was identified as those which fired low-threshold spikes (LTS cells) from hyperpolarized potentials, were positive for somatostatin and nitric oxide synthase (NOS), and had the largest axonal fields. The other class of interneurons had longer-lasting afterhyperpolarizations (LA cells), were positive for choline acetyltransferase, and were mostly large aspiny cells. Glutamic acid decarboxylase (GAD67) or GABA immunoreactivity was detected at the somata or terminals of parvalbumin FS cells and somatostatin/NOS LTS cells, but not of cholinergic LA cells. Substance P, probably released from the collaterals of cells projecting to the substantia nigra, excited LA cells and LTS cells, but not FS cells. These results suggest that the striatum has at least one type of cholinergic and two types of GABAergic interneurons which are different in physiological, chemical and pharmacological characteristics.
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PMID:Cholinergic and GABAergic interneurons in the striatum. 920 28

This study examined the effects of chronic intrastriatal infusion of L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a selective competitive inhibitor of high affinity glutamate transport systems, via osmotic minipumps in rats. Injection of PDC at the rate of 25 nmol/h for 14 days caused striatal lesion. Histological evaluation on frontal striatal sections showed that the lesion was circumscribed to a circular area showing a dramatic neuronal loss accompanied by gliosis and representing 30% of the whole striatal surface at the level of the injection site. A total loss of neurons expressing glutamate decarboxylase (GAD67), enkephalin or substance P mRNA was observed on a similar circular area, suggesting degeneration of the two populations of striatal efferent neurons. In the whole striatum outside the region devoided of hybridization signal, a selective 27% decrease in enkephalin mRNA expression occurred, suggesting a higher sensitivity of enkephalin neurons versus substance P neurons to glutamate uptake-mediated alterations. Injection of PDC at the rate of 25 nmol/h for 3 days produced striatal lesion of similar extent. In contrast, PDC at the rate of 5 nmol/h did not produce neuronal damage when administered over 14 days. This study provides new in vivo evidence that defective glutamate transport is one of the critical conditions that may give rise to toxicity of an endogenous transmitter system in the striatum, and may underlie neuronal death in neurodegenerative diseases.
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PMID:Continuous administration of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate produces striatal lesion. 940 33

Rats sustaining unilateral near-complete 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received daily injections of 3, 4 dihydroxyphenyl-l-alanine (L-DOPA, 8 mg/kg plus 15 mg/kg benserazide) for 3 weeks. During this period, about 50% of the rats gradually developed abnormal involuntary movements, lasting for 2-3 h following each L-DOPA dose. Rats were killed 3 days after the last L-DOPA injection, and sections through the striatum were processed for in situ hybridization histochemistry. Within the L-DOPA-treated group, levels of preproenkephalin (PPE) mRNA, glutamic acid decarboxylase (GAD67) mRNA, and prodynorphin (PDyn) mRNA in the dopamine-denervated caudate-putamen, as well as GAD67 mRNA expression in the globus pallidus ipsilateral to the 6-hydroxydopamine (6-OHDA) lesion, were higher in dyskinetic than non-dyskinetic animals, and positively correlated with the rats' dyskinesia scores. By contrast, striatal preprotachykinin mRNA expression and D2 receptor-radioligand binding were not significantly associated with dyskinesia. Among all these markers, PDyn mRNA levels showed the most pronounced treatment-dependence (three times higher in the L-DOPA-treated group than in saline-injected lesion-only controls), and the strongest correlation with the rats' dyskinesia scores (r2 = 0.82). However, a multiple regression equation including the three factors, GAD67 mRNA levels in the GP, GAD67 mRNA in the lateral CPu, and striatal PDyn mRNA, gave a better fit for dyskinesia scores than PDyn mRNA alone (r2 = 0.92). The results show that L-DOPA-induced dyskinesia is associated with overexpression of PDyn and GAD67 mRNA in the striatal projection neurons, and GAD67 mRNA levels in the globus pallidus. Due to its treatment-dependent expression, and strong correlation with the associated dyskinetic symptoms, striatal PDyn mRNA, in particular, may play a role in the mechanisms of behavioural sensitization brought about by the drug.
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PMID:L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA. 976 99

The striatum is regulated by dopaminergic inputs from the substantia nigra. Several anatomical studies using in situ hybridization have demonstrated that in rodents, dopamine D1 and D2 receptors are segregated into distinct striatal efferent populations: dopamine D1 receptor into gamma-aminobutyric acid (GABA)/substance P striatonigral neurons, and dopamine D2 receptor into GABA/enkephalin striatopallidal neurons. The existence of such a segregation has not been investigated in primates. Therefore, to quantify the efferent striatal GABAergic neurons in the adult Cynomolgus monkey, we detected GAD67 mRNA expression while considering that only a minority of the GABAergic population is composed of interneurons. To characterize the peptidergic phenotype of the neurons expressing dopamine D1 or D2 receptors, we examined the mRNA coding for these receptors in the striatum at the cellular level using single- and double in situ hybridization with digoxigenin and 35S ribonucleotide probes. Double in situ hybridization demonstrated a high coexpression of dopamine D1 receptor and substance P mRNAs (91-99%) as well as dopamine D2 receptor and preproenkephalin A mRNAs (96-99%) in medium-sized neurons throughout the nucleus caudatus, putamen, and nucleus accumbens. Only a small subpopulation (2-5%) of the neurons that contained dopamine D1 receptor mRNA also expressed dopamine D2 receptor mRNA in all regions. Large-sized neurons known to be cholinergic expressed D2R mRNA. However, within the nucleus basalis of Meynert, the large cholinergic neurons expressed D2R mRNA, but the neurons producing enkephalin expressed neither D1R nor D2R mRNA. These results demonstrate that the striatal organizational pattern of D1 and D2 receptor segregation in distinct neuronal populations described in rodent also exists in primate.
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PMID:Phenotypical characterization of the neurons expressing the D1 and D2 dopamine receptors in the monkey striatum. 1070 53

Huntington's disease is a devastating progressive neurodegenerative illness characterized by massive neuronal loss in the striatum. It is caused by the presence of an expanded CAG repeat in the gene encoding huntingtin, a protein of unknown function. We have examined the expression of neurotransmitters and other antigens present in striatal neurons with immunohistochemistry, and the level of expression of mRNAs encoding enkephalin, substance P, and glutamic acid decarboxylases with quantitative in situ hybridization histochemistry, in the striatum of two mouse models of Huntington's disease: transgenic animals expressing exon 1 of the human huntingtin gene with 144 CAG repeats and "knock-in" mice containing a chimeric mouse/human exon 1 with 71 or 94 CAG repeats inserted by homologous targeting. Although the transgenic (but not the knock-in) mice were previously shown to display prominent huntingtin- and ubiquitin-containing nuclear inclusions in striatal neurons, in situ nick translation followed by emulsion autoradiography did not reveal any DNA damage in striatum or cortex in these mice. Immunolabeling for calbindin D 28K, enkephalin, substance P, glutamic acid decarboxylases (M(r) 65,000 or 67,000, GAD65 and GAD67), somatostatin, choline acetyltransferase, parvalbumin, and glial fibrillary acidic protein were remarkably similar in transgenic, knock-in, and wild-type mice. Both transgenic and knock-in mice, however, showed a marked decrease in the level of expression of enkephalin mRNA in striatal neurons without significant decreases in mRNAs encoding substance P, GAD65, or GAD67. The data indicate that decreased expression of enkephalin mRNA may be an early sign of neuronal dysfunction due to the Huntington's disease mutation.
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PMID:Decrease in striatal enkephalin mRNA in mouse models of Huntington's disease. 1073 39

Double-label in situ hybridization was used to identify the phenotypes of striatal neurons that express mRNA for cannabinoid CB(1) receptors. Simultaneous detection of multiple mRNAs was performed by combining a (35)S-labeled ribonucleotide probe for CB(1) mRNA with digoxigenin-labeled riboprobes for striatal projection neurons (preprotachykinin A, prodynorphin, and preproenkephalin mRNAs) and interneurons (vesicular acetylcholine transporter (VAChT), choline acetyltransferase (ChAT), somatostatin, and glutamic acid decarboxylase (Mr 67,000; GAD67) mRNAs). To ascertain whether CB(1) mRNA was a marker for striatal efferents, digoxigenin-labeled probes for mRNA markers of both striatonigral (prodynorphin or preprotachykinin A mRNAs), and striatopallidal (proenkephalin mRNAs) projection neurons were combined with the (35)S-labeled probe for CB(1). A mediolateral gradient in CB(1) mRNA expression was observed at rostral and mid-striatal levels; in the same coronal sections the number of silver grains per cell ranged from below the threshold of detectability at the medial and ventral poles to saturation at the dorsolateral boundary bordered by the corpus callosum. At the caudal level examined, CB(1) mRNA was denser in the ventral sector relative to the dorsal sector. Virtually all neurons expressing mRNA markers for striatal projection neurons colocalized CB(1) mRNA. Combining a (35)S-labeled riboprobe for CB(1) with digoxigenin-labeled riboprobes for both preproenkephalin and prodynorphin confirmed localization of CB(1) mRNA to striatonigral and striatopallidal neurons expressing prodynorphin and preproenkephalin mRNAs, respectively. However, CB(1) mRNA-positive cells that failed to coexpress the other markers were also apparent. CB(1) mRNA was localized to putative GABAergic interneurons that express high levels of GAD67 mRNA. These interneurons enable functional interactions between the direct and indirect striatal output pathways. By contrast, aspiny interneurons that express preprosomatostatin mRNA and cholinergic interneurons that coexpress ChAT and VAChT mRNAs were CB(1) mRNA-negative. The present data provide direct evidence that cannabinoid receptors are synthesized in striatonigral neurons that contain dynorphin and substance P and striatopallidal neurons that contain enkephalin. By contrast, local circuit neurons in striatum that contain somatostatin or acetylcholine do not synthesize cannabinoid receptors. Published 2000 Wiley-Liss, Inc.
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PMID:Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. 1084 53


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