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)

The effects of dopamine agonists and antagonists on rat basal ganglia substance P, substance K, and preprotachykinin mRNA were examined. Chronic administration of the prototypical dopamine antagonist haloperidol decreased striatal preprotachykinin mRNA and nigral tachykinin peptides. Chronic treatment with the dopamine D2 receptor antagonist L-sulpiride (but not the inactive D-isomer) mimicked the effect of haloperidol. In contrast, the atypical neuroleptic clozapine did not decrease tachykinin mRNA or peptides. The potent indirect dopamine agonist methamphetamine rapidly increased preprotachykinin mRNA, substance P, and substance K although the direct agonist apomorphine was without effect. Methamphetamine-stimulated changes in preprotachykinin mRNA were prevented by prior haloperidol administration. These data demonstrate that alterations in dopaminergic transmission significantly alter striatonigral tachykinin biosynthesis in vivo.
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PMID:Striatal tachykinin biosynthesis: regulation of mRNA and peptide levels by dopamine agonists and antagonists. 244 8

This study employed in situ hybridization to directly compare the effects of cocaine and methamphetamine on neurotensin/neuromedin N and preprotachykinin messenger RNAs in distinct striatal regions. Male, Sprague-Dawley rats received a single administration of 15mg/kg methamphetamine (s.c.) or 30mg/kg cocaine (i.p.) and were killed 30min or 3h later. Methamphetamine and cocaine produced significant increases in preprotachykinin messenger RNA in the striatum after 3h, but often in different subregions. Both drugs produced similar effects on preprotachykinin messenger RNA in the rostral striatum. However, methamphetamine produced significant increases in all regions of the caudal striatum, whereas cocaine-induced preprotachykinin messenger RNA expression was limited to dorsal regions of this striatal area. Methamphetamine also produced a significant increase in preprotachykinin messenger RNA in the caudal striatum after 30min, whereas cocaine had no significant effect on preprotachykinin messenger RNA at this early time-point. The pattern of changes in neurotensin/neuromedin N messenger RNA caused by methamphetamine and cocaine after 3h was even more distinct. Cocaine produced significant increases in neurotensin/neuromedin N messenger RNA in all regions of the rostral striatum, whereas methamphetamine had no effect in these areas. Furthermore, in more caudal sections, cocaine predominantly affected neurotensin/neuromedin N expression in dorsal aspects of the striatum, whereas methamphetamine significantly increased neurotensin/neuromedin N messenger RNA in all regions. There was much less effect of either drug on neuropeptide expression in the nucleus accumbens. The only significant effect was an increase in neurotensin/neuromedin N messenger RNA in the core region 3h after methamphetamine administration. These results indicate that methamphetamine and cocaine increase preprotachykinin and neurotensin/neuromedin N messenger RNAs in distinct regions of the striatum. The ability of methamphetamine and cocaine to alter neuropeptide messenger RNA expression in unique regions of the striatum may be important for the long-term effects of these drugs, such as sensitization, since the striatum is not homogeneous in its connections and function.
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PMID:Differential effects of cocaine and methamphetamine on neurotensin/neuromedin N and preprotachykinin messenger RNA expression in unique regions of the striatum. 1118 47

We studied the role of the peptide substance P, signaling through the neurokinin-1 (NK-1) receptor, on methamphetamine-induced loss of dopamine transporter sites, a well-documented marker of toxicity in the striatum of the mouse brain, because this peptide is under dynamic regulation by the neurotransmitter dopamine. Methamphetamine is a psychostimulant that induces dopamine overflow from dopamine terminals of the striatum. Mice were given four injections of methamphetamine (7.5 mg/kg of body weight) at two-hour intervals and were sacrificed three days after the treatment. Dopamine transporter levels in the striatum were assessed by receptor autoradiography with [(125)I]RTI-121. Exposure to methamphetamine resulted in significant loss of dopamine transporters in the caudate-putamen. This loss was prevented by preexposure (30 min before the first injection of methamphetamine) of the neurokinin-1 receptor antagonist L-733,060. The inactive enantiomer of L-733,060 (L-733,061) failed to protect dopamine transporter sites from methamphetamine, suggesting specificity for the neurokinin-1 receptor. Moreover, the protective effect of L-733,060 was observed in mice that were 10 weeks of age or older (dopamine transporter sites in mice six and eight weeks old were not protected from methamphetamine by the neurokinin-1 receptor antagonist). The results demonstrate that the deleterious effect of methamphetamine on dopamine transporter sites of the striatum is mediated via the neurokinin-1 receptor. The involvement of the NK-1 receptor appears after the eighth week of postnatal life, suggesting that the link between dopamine transporters and the neurokinin-1 receptor becomes functional at approximately the time when the mouse reaches reproductive age.
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PMID:Ontogeny of neurokinin-1 receptor mediation of methamphetamine neurotoxicity in the striatum of the mouse brain. 1210

Methamphetamine (METH) is an addictive substance that also causes extensive neural degeneration in the central nervous system. Because METH augments striatal substance P (SP) levels, we hypothesized that this neuropeptide plays a role in methamphetamine-induced toxicity and neural damage in the striatum. In this study we present evidence demonstrating that signaling through the neurokinin-1 (NK-1) receptor by SP plays an important role in methamphetamine-induced toxicity in the striatum. We tested the effects of the selective NK-1 receptor antagonists WIN-51,708 and L-733,060 on several markers of dopaminergic terminal toxicity in the mouse striatum. Administration of NK-1 receptor antagonist prevented the loss of dopamine transporters assessed by autoradiography and western blotting, the loss of tissue dopamine assessed by high-pressure liquid chromatography, and the loss of tyrosine hydroxylase, as well as the induction of glial fibrillary acidic protein determined by western blotting. Pre-treatment with NK-1 receptor antagonist had no effect on METH-induced hyperthermia. Pre-exposure of mice to either of the NK-1 receptor antagonists alone was without effect on all of these neurochemical markers. These results provide the first evidence that tachykinins, particularly SP, acting through NK-1 receptors, play a crucial role in the pathogenesis of nigrostriatal dopaminergic terminal degeneration induced by METH. This finding could lead to novel therapeutic strategies to offset drug addictions as well as in the treatment of a number of disorders including Parkinson's and Huntington's diseases.
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PMID:Neurokinin-1 (NK-1) receptor antagonists abrogate methamphetamine-induced striatal dopaminergic neurotoxicity in the murine brain. 1239 May 23

We have explored the effect of histamine H3-receptor ligands on the regulation of neuropeptide mRNA expression in the striatum by using in situ hybridization performed with proenkephalin, prodynorphin, substance P and proneurotensin riboprobes. Acute administration of ciproxifan, an H3-receptor antagonist/inverse agonist, or (R)-alpha-methylhistamine, an H3-receptor agonist, did not modify the striatal expression of the neuropeptides by itself. However, ciproxifan strongly and differentially modulated the effect of a single administration of 3 mg/kg methamphetamine on neuropeptide mRNA expression. This modulation was suppressed by the administration of (R)-alpha-methylhistamine and occurred in both the caudate-putamen and nucleus accumbens. Ciproxifan strongly potentiated the decrease of proenkephalin mRNA expression induced by methamphetamine. In contrast, it suppressed the increase in prodynorphin and substance P mRNA expression induced by methamphetamine. Methamphetamine alone or with ciproxifan did not modify proneurotensin mRNA expression. These neurochemical findings indicate that ciproxifan differentially regulates the effect of methamphetamine on the neuropeptides contained in striatonigral and striatopallidal neurons. They suggest that endogenous histamine and dopamine cooperate to modulate the activity of striatal projection neurons and strengthen the interest of H3-receptors as new targets for the treatment of psychotic disorders and drug abuse.
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PMID:Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, modulates the effects of methamphetamine on neuropeptide mRNA expression in rat striatum. 1254 67

Methamphetamine (METH) is an addictive psychostimulant that induces damage to the dopamine terminals and the apoptosis of some neurons of the striatum. Our laboratory demonstrated using either a single bolus dose (30 mg/kg) or a binge (10 mg/kg 4x at 2-h intervals) of METH that pharmacological blockade of the substance P receptor (neurokinin-1) attenuates METH-induced damage to both the presynaptic dopamine terminals and the apoptosis of some neurons of the striatum. To determine the phenotype of striatal neuron ablated by METH, we combined TUNEL (Terminal Deoxyncleotidyl Transferase-Mediated dUTP Nick End Labeling) with immunofluorescence for selective markers of projection and interneurons. METH induces the loss of approximately 20% of the projection neurons. The cholinergic and gamma-aminobutyric acid (GABA)-parvalbumin interneurons sustain losses of 30% and 50%, respectively. The somatostatin/neuropeptide Y (NPY)/nitric oxide synthase (NOS) interneurons are not impacted by METH. To investigate the mechanism by which substance P mediates METH-induced damage in this part of the brain, we ablated the striatal interneurons that express the neurokinin-1 receptor (NK-1R) with the selective neurotoxin substance P-SAP. Ablation of the NK-1R-expressing interneurons prevented METH-induced apoptosis in the striatum but was without effect on depletion of dopamine terminal markers. We propose that substance P mediates the apoptosis of some striatal neurons via the intrastriatal activation of nitric oxide synthesis. In contrast, substance P may mediate damage of the dopamine terminals via an extrastriatal mechanism involving the substantia nigra and cortical glutamate release.
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PMID:Distinct mechanisms mediating methamphetamine-induced neuronal apoptosis and dopamine terminal damage share the neuropeptide substance p in the striatum of mice. 1710 11

Methamphetamine (METH) is a psychostimulant that induces long-term deficits of dopamine terminal markers and apoptotic cell death in the striatum. Our laboratory demonstrated that pharmacological blockade of the neurokinin-1 receptor attenuated the METH-induced damage to the striatal dopamine terminals and the apoptotic cell death of some striatal neurons. Here, we used histological methods to assess the effect of METH on neurokinin-1 receptor trafficking in the striatum as an indirect index of signaling by the neuropeptide substance P (natural ligand for this receptor). Male mice received a single injection of METH (30 mg/kg, i.p.) and were sacrificed 30 min later. Immunohistofluorescence confocal microscopy confirmed that the neurokinin-1 receptor is located on cholinergic and somatostatin interneurons of the striatum. METH induced the trafficking of the neurokinin-1 receptor from the membrane into cytoplasmic endosomes primarily in the somatostatin/NPY/NOS interneurons, and this phenomenon was attenuated by antagonists of the dopamine D1 (SCH-23390), D2 (raclopride), or neurokinin-1 (WIN-51,708) receptors. These data demonstrate that METH induces the trafficking of the striatal neurokinin-1 receptors principally in the somatostatin/NPY/NOS interneurons and that this phenomenon is dependent on the activity of dopamine D1 and D2 receptors.
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PMID:Methamphetamine induces striatal neurokinin-1 receptor endocytosis primarily in somatostatin/NPY/NOS interneurons and the role of dopamine receptors in mice. 2073 Aug 2

Methamphetamine (METH) is a potent stimulant that induces both acute and long-lasting neurochemical changes in the brain including neuronal cell loss. Our laboratory demonstrated that the neuropeptide substance P enhances the striatal METH-induced production of nitric oxide (NO). In order to better understand the role of the striatal neuropeptides on the METH-induced production of NO, we used agonists and antagonists of the NPY (Y1R and Y2R) receptors infused via intrastriatal microinjection followed by a bolus of METH (30 mg/kg, ip) and measured 3-NT immunofluorescence, an indirect index of NO production. One striatum received pharmacological agent while the contralateral striatum received aCSF and served as control. NPY receptor agonists dose dependently attenuated the METH-induced production of striatal 3-NT. Conversely, NPY receptor antagonists had the opposite effect. Moreover, METH induced the accumulation of cyclic GMP and activated caspase-3 in approximately 18% of striatal neurons, a phenomenon that was attenuated by pre-treatment with NPY2 receptor agonist. Lastly, METH increased the levels of striatal preproneuropeptide Y mRNA nearly five-fold 16 h after injection as determined by RT-PCR, suggesting increased utilization of the neuropeptide. In conclusion, NPY inhibits the METH-induced production of NO in striatal tissue. Consequently, production of this second messenger induces the accumulation of cyclic GMP and activated caspase-3 in some striatal neurons, an event that may precede the apoptosis of some striatal neurons.
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PMID:Modulation of methamphetamine-induced nitric oxide production by neuropeptide Y in the murine striatum. 2298 89

Methamphetamine-induced partial dopamine depletions are associated with impaired basal ganglia function, including decreased preprotachykinin mRNA expression and impaired transcriptional activation of activity-regulated, cytoskeleton-associated (Arc) gene in striatum. Recent work implicates deficits in phasic dopamine signaling as a potential mechanism linking methamphetamine-induced dopamine loss to impaired basal ganglia function. This study thus sought to establish a causal link between phasic dopamine transmission and altered basal ganglia function by determining whether the deficits in striatal neuron gene expression could be restored by increasing phasic dopamine release. Three weeks after pretreatment with saline or a neurotoxic regimen of methamphetamine, rats underwent phasic- or tonic-like stimulation of ascending dopamine neurons. Striatal gene expression was examined using in situ hybridization histochemistry. Phasic-like, but not tonic-like, stimulation induced immediate-early genes Arc and zif268 in both groups, despite the partial striatal dopamine denervation in methamphetamine-pretreated rats, with the Arc expression occurring in presumed striatonigral efferent neurons. Phasic-like stimulation also restored preprotachykinin mRNA expression. These results suggest that disruption of phasic dopamine signaling likely underlies methamphetamine-induced impairments in basal ganglia function, and that restoring phasic dopamine signaling may be a viable approach to manage long-term consequences of methamphetamine-induced dopamine loss on basal ganglia functions.
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PMID:Phasic-like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine-induced partial dopamine denervation. 2348 Jan 99