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 blockade of the dopamine (DA) D2 receptor by repeated systemic administration of the butyrophenone neuroleptic, haloperidol (HAL), is known to lead to a decrease in levels of the neuroactive peptide, substance P (SP), in the rat striatum and substantia nigra (SN). Using a high-resolution, quantitative radioimmunocytochemistry (RIC) technique, we have shown the HAL-induced decrease in rat nigral SP to be both dose- and time-dependent. In addition, chronic administration of the highly selective D2 antagonist, S(-)-sulpiride, also decreased nigral SP. Following blockade of the dopamine D1 receptor by chronic administration of the selective D1 antagonist, SCH 23390, we found, in contrast, that levels of SP in SN were increased in a dose- and time-dependent fashion. The magnitude of the maximum SCH 23390-induced elevation (20-30%) of nigral SP was approximately equal to that of the maximum HAL-induced decrease. The opposite response of nigral SP levels to repeated injections of a D1 or D2 antagonist suggests that the two DA receptor subtypes exert tonic, opposing, modulatory influences on the SP content of the striatonigral pathway.
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PMID:Quantitative radioimmunocytochemical evidence that haloperidol and SCH 23390 induce opposite changes in substance P levels of rat substantia nigra. 245 1

The influence of the acute (single dose) or subchronic (one dose daily for 4 days) administration of cocaine to Sprague-Dawley rats on striatal enkephalin (Met5-enkephalin) and striatonigral tachykinin (substance P) and dynorphin [dynorphin A (1-8), DYN] levels was investigated. The peptide levels were determined by radioimmunoassay. The concentrations of the striatal levels of dopamine (DA), 5-hydroxytryptamine and their acid metabolites were determined by high-performance liquid chromatography with electrochemical detection. An acute administration of cocaine (20 or 30 mg/kg i.p.) did not affect the peptide levels in the striatum or in the substantia nigra. A regimen of subchronic administration of cocaine (20 mg/kg/day for 4 days) increased the striatonigral DYN levels, without altering the levels of Met5-enkephalin or substance P. The increase in DYN levels were persistent for at least 4 days after the last dose of the subchronic administration of cocaine. The DYN levels returned to control values by 12 days after the last dose. The DA levels in the striatum were increased 30 min after a single dose of cocaine. None of the other treatments elicited any changes in DA or 5-hydroxytryptamine or their metabolites. The subchronic cocaine administration to dopaminergic denervated rats with 6-hydroxydopamine failed to evoke any increase in DYN levels in the striatum or substantia nigra. The concurrent administration of the D1 DA antagonist, SCH-23390, or the D2 DA antagonist, spiperone, to the subchronic regimen of cocaine also blocked the cocaine-induced increase in DYN levels. These results indicate that cocaine selectively enhances the synthesis or decreases the release of DYN in the striatonigral neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cocaine selectively increases striatonigral dynorphin levels by a dopaminergic mechanism. 247 48

The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder. Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, L-dihydroxyphenylalanine (L-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64%) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28%). The L-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the L-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation: and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.
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PMID:D1 dopamine receptor-mediated substance P depletion in the striatonigral neurons of rats subjected to neonatal dopaminergic denervation: implications for self-injurious behavior. 248 60

The involvement of D-1 and D-2 dopamine (DA) receptors in mediating the DA regulation of preprotachykinin (PPT) gene expression was investigated in rat striatal tissue. Initial experiments determined that acute treatment with the indirect DA agonist methamphetamine induces increases in total PPT messenger RNA, with a maximal effect seen within 3 hr. RNA protection studies established that acute methamphetamine treatment did not affect the relative ratios of the various PPT gene transcripts derived by alternate splicing. The methamphetamine-induced increase in total PPT messenger RNA could be blocked by either a D-1 or a D-2 selective DA antagonist (SCH 23390 and sulpiride, respectively). The D-2 agonist quinpirole, but not the D-1 agonist SKF 38393, mimicked the methamphetamine-induced increase. This D-2 agonist-induced increase was dependent upon D-1 receptor tone, as either co-administration of SCH 23390 or pretreatment with the DA synthesis inhibitor alpha-methyltyrosine blocked the quinpirole-induced increase. These studies provide biochemical evidence for an enabling role of D-1 DA receptors in striatal D-2 DA receptor function.
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PMID:Striatal tachykinin gene expression regulated by interaction of D-1 and D-2 dopamine receptors. 252 3

Iodinated SCH 23390, [125I]SCH 23982, saturably binds in brain to D1 receptors that mostly reside on striatal and striatonigral neurons. [125I]SCH 23982 autoradiography was used to determine the topography of D1 receptor-containing striatal inputs to subregions of the substantia nigra. The concentration of D1 sites was greatest in the pars reticulata of the substantia nigra and exceeded by over 50% the equal concentrations of D1 sites in the lateral substantia nigra, caudate-putamen, nucleus accumbens, and olfactory tubercle. D1 receptors were uniformly concentrated throughout the caudate-putamen and were absent in the pars compacta of the substantia nigra and ventral tegmental area. Injections into the rostral striatum of the axon-sparing neurotoxin, quinolinic acid, depleted the concentration of D1 sites in the rostral caudate-putamen by 98% and the concentration of D1 sites in the medial substantia nigra by up to 74%. Quinolinic acid-induced losses of the D1 sites in the central striatum of up to 85% were associated with 87% losses of D1 sites in the central nigra. D1 losses of 91% in the caudal striatum were associated with D1 losses of 85% in the lateral nigra. Thus, most D1 sites in the striatum reside on neurons that are intrinsic to that brain region, and the vast majority of D1 sites in the substantia nigra are on the terminals of striatonigral neurons. These D1 receptor-containing striatonigral neurons have a rostral, central, or caudal origin in the striatum and a corresponding medial, central, or lateral termination in the nigra. This topographical organization of striatal inputs to the substantia nigra indicates that substance P or dynorphin B-containing striatonigral neurons may have D1 receptors on their terminals.
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PMID:Topography of substantia nigra innervation by D1 receptor-containing striatal neurons. 295 7

The regulation of tachykinin-evoked acetylcholine release by the dopaminergic system in the neostriatum was examined. We studied the effect of selective and potent tachykinin agonists for each subtype of receptor ([Sar9,Met(O2)11]-Substance P for NK1; [Nle10]-Neurokinin A4-10 for NK2; and senktide for NK3) on endogenous acetylcholine release from rat striatal slices where the dopaminergic system was modified either by 6-hydroxydopamine lesion or by dopamine receptor antagonists. Unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway induced a decrease in senktide-evoked acetylcholine release and an increase in the effect of [Nle10]-Neurokinin A4-10. The same results were obtained after chronic haloperidol treatment, whereas SCH-23390 or clozapine treatment had no effect on tachykinin-evoked acetylcholine release, suggesting an involvement of D2 receptors. 6-hydroxydopamine lesion induced a diminution in the density of NK3 receptor, which could be related to the reduction in senktide-evoked acetylcholine release.
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PMID:Control of tachykinin-evoked acetylcholine release from rat striatal slices by dopaminergic neurons. 750 58

The effect of acute subcutaneous administration of methamphetamine on the expression of neurotensin mRNA was investigated in the adult rat striatum. At different time points (2, 6 and 24 h) following drug administration rats were killed, and mRNA levels were quantified both on films and emulsion-dipped tissue sections from two striatal levels. Two hours after methamphetamine injection, a dramatic increase in neurotensin mRNA levels was detected in different areas of the striatum at both rostral and caudal levels. Numerous positive cells were observed in the dorsomedial, dorsolateral and ventrolateral parts of the striatum. This up-regulation reflected an increase both in the number of cells expressing neurotensin mRNA and in the mean mRNA levels. This increase was still present after 6 h and was similar to the 2 h treated group at the rostral level of the striatum, but lower at the caudal one. Twenty-four hours after methamphetamine injection, neurotensin mRNA levels were back to control values, or in some areas even below. A strong increase in neurotensin mRNA-expressing cells was also seen in the olfactory tubercle, and the time-course was similar to the one observed in the striatum. In a second set of experiments, the effect of methamphetamine was evaluated on adjacent striatal sections hybridized with probes directed against neurotensin and substance P mRNAs, respectively. Two hours after drug administration, a significant increase in the levels of both peptide mRNAs was observed (+190% for neurotensin, +80% for substance P). These results demonstrate that methamphetamine is able to induce a dramatic, rapid and transient increase in striatal neurotensin mRNA levels, which may partly account for the elevation in neurotensin peptide levels observed in the striatonigral pathway after methamphetamine. The different anatomical localization of neurotensin mRNA-expressing cells observed after haloperidol and methamphetamine treatments, as well as the fact that the D1 receptor antagonist SCH-23390 is able to counteract the effect of methamphetamine but not that of haloperidol on neurotensin mRNA expression, suggests that there are at least two different subpopulations of neurotensin cells in the striatum. One population is regulated via D1 receptors and projects to the substantia nigra pars reticulata. The second is sensitive to D2 receptor stimulation and may project to the globus pallidus and/or may represent interneurons.
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PMID:Up-regulation of neurotensin mRNA in the rat striatum after acute methamphetamine treatment. 751 73

Central dopaminergic systems have been implicated in the regulation of blood pressure. We examined the effect on blood pressure of electrical or chemical stimulation of the rat brain ventral tegmental area (VTA) which is the region of origin of the A10 dopaminergic system. Electrical stimulation in urethane-anaesthetised rats (10-120 Hz, 80 microA) produced frequency-dependent increases in blood pressure (max 30-35 mmHg). These pressor responses could be significantly attenuated by pretreatment with the dopamine D2 receptor antagonist haloperidol, but not the D1 receptor antagonist SCH 23390. Chemical stimulation of the VTA, by microinjection of 10 nmol of the substance P analogue DiMe-C7, produced a sustained increase in blood pressure (max 10-15 mmHg), which could be completely prevented by pretreatment with haloperidol. These results suggest that stimulation of dopaminergic neurons in the VTA induces pressor responses and that projections from midbrain dopaminergic neurons, acting on dopamine D2 receptors, play a role in the regulation of blood pressure.
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PMID:Pressor responses to electrical and chemical stimulation of the rat brain A10 dopaminergic system. 753 Mar 50

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

The ability of the substance P (NK1) receptor antagonist CP-99,994 to alter catalepsy induced by a dopamine D1 or D2 receptor antagonist and the ability of CP-99,994 to influence acetylcholine (ACh) release in the striatum were investigated in rats. Catalepsy produced by the D1 antagonist SCH 23390 (0.5 mg/kg s.c.) was not altered by CP-99,994 (0.5, 2.5, or 10 mg/kg s.c.). In contrast, catalepsy induced by the D2 antagonist raclopride (2.5 mg/kg i.p.) was attenuated by CP-99,994 (2.5 and 10 mg/kg). CP-99,994 (10 mg/kg) did not stimulate locomotion when given alone. The less active enantiomer of CP-99,994, CP-100,263 (10 mg/kg), did not alter raclopride-induced catalepsy. Both systemic administration and intrastriatal perfusion of CP-99,994 alone decreased striatal ACh release. Bilateral intrastriatal perfusion of CP-99,994 (40 and 100 microM) reduced catalepsy produced by raclopride and attenuated raclopride-induced increases in striatal ACh release. The reductions in the duration of catalepsy and decreases in striatal ACh release associated with CP-99,994 perfusion were positively correlated. These findings suggest that blockade of striatal NK1 receptors reduces catalepsy induced by a dopamine D2 antagonist, an effect mediated, at least in part, by reducing striatal ACh release. Striatal NK1 receptors, therefore, may be a new therapeutic target for developing drugs that alleviate motor side effects associated with antipsychotic treatment.
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PMID:The neurokinin1 receptor antagonist CP-99,994 reduces catalepsy produced by the dopamine D2 receptor antagonist raclopride: correlation with extracellular acetylcholine levels in striatum. 763 56


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