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

In the central nervous system (CNS), dopamine is involved in the control of locomotion, cognition, affect and neuroendocrine secretion. These actions of dopamine are mediated by five different receptor subtypes, which are members of the large G-protein coupled receptor superfamily. The dopamine receptor subtypes are divided into two major subclasses: the D1-like and D2-like receptors, which typically couple to Gs and Gj mediated transduction systems. In the CNS, the various receptor subtypes display specific anatomical distributions, with D1-like receptors being mainly post-synaptic and D2-like receptors being both pre- and post-synaptic. D1 and D2 dopamine receptors, the most abundant subtypes in the CNS, appear to be expressed largely in distinct neurons. Substance P and dynorphin, which are expressed in D1 receptor-containing neurons, as well as pre-proenkephalin in D2 receptor-containing neurons, have been used as monitors of dopaminergic activity in the CNS. Expression of immediate early genes, in particular fos, has also been found to correlate with dopaminergic transmission. Dopamine released from the hypothalamus controls the synthesis and secretion of prolactin from the anterior pituitary via D2 dopamine receptors. As yet none of the dopamine receptor subtypes have been associated with the etiology of psychotic disorders, such as schizophrenia. However, the recent characterization of D3 and D4 receptors which are, interestingly, expressed in areas of the CNS mediating cognition and affect or showing increased affinity for certain neuroleptics, have renewed the interest and hope of finding effective neuroleptics devoid of side effects. Finally, the recent production of genetically-derived animals lacking several of these receptor genes should help elucidate which specific physiological paradigms the receptors mediate.
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PMID:Dopamine receptors and brain function. 902 98

Primary cultures of gerbil mesencephalon were used for studying the modulation exerted by tachykinin NK(3) receptor activation on the activity of dopamine (DA) neurons. Dopamine neurons were identified by their ability to take up [(3)H]DA in a nomifensine-dependent manner. Moreover, tyrosine hydroxylase immunohistochemistry revealed that these neurons accounted for 5-7% of the total cell population. The NK(3) receptor agonists, senktide (EC(50) = 0.58 nM) and [MePhe(7)]neurokinin B (EC(50) = 3 nM), increased spontaneous [(3)H]DA release in a concentration-dependent manner. In contrast, tested at a supramaximal concentration (IC(50) = 0.89 nM), neither septide nor substance P were found to affect [(3)H]DA release. The senktide-evoked [(3)H]DA release was not observed when extracellular Ca(2+) was chelated, but was unaffected by nomifensine. This indicates that this increase in [(3)H]DA outflow resulted more from an exocytotic process than from reversal of carrier-mediated DA uptake. Moreover, the senktide effect was unaffected by the Na+ channel blocker tetrodotoxin, a result suggesting a direct action of senktide on DA neurons. The non-peptide NK(3) receptor antagonist, SR 142801, shifted or blocked (IC(50) = 0.89 nM) the senktide-evoked [(3)H]DA release, while its (-)-antipode, SR 142806, was 80-fold less potent, in agreement with binding data. Selective antagonists for Nk1 (SR 140333) or Nk2 (SR 48968) receptors failed to reduce the senktide effect. Light scanning microscopic analysis of mesencephalic cells loaded with the Ca(2+) sensitive dye, fluo-3, showed that senktide induced a rise in cytosolic Ca(2+) in 8-10% of the cell population. The senktide-induced elevation in intracellular Ca(2+) was rapid in onset and transient (at 10-8 M) or more sustained with no further increase in fluorescence intensity (at 10(-7) M). The proportion of senktide-responsive cells was not significantly modified when extracellular Ca(2+) was chelated, but was reduced by 87% in the presence of SR 142801 and by 75% in cultures that were pre-treated with the DA neurotoxin 1-methyl-4-phenylpyridinium. The present study shows that enhancement of spontaneous [(3)H]DA release and intracellular Ca(2+) mobilization may be observed after NK(3) receptor stimulation and that both biochemical events are likely to occur in DA neurons.
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PMID:Evidence for modulation of dopamine-neuronal function by tachykinin NK3 receptor stimulation in gerbil mesencephalic cell cultures. 908 31

The chemical phenotype of proneurotensin messenger RNA-expressing cells was determined in the acute haloperidol-treated rat striatum using a combination of (35S)-labelled and alkaline phosphatase-labelled oligonucleotides. Cellular sites of proneurotensin messenger RNA expression were visualized simultaneously on tissue sections processed to reveal cellular sites of preproenkephalin A messenger RNA or the dopamine and adenylate cyclase phosphoprotein-32, messenger RNA. The cellular co-expression of preproenkepahlin A (enkephalin) and preprotachykinin (substance P) messenger RNA was also examined within forebrain structures. Cellular sites of enkephalin (substance P) and dopamine and adenylate cyclase phosphoprotein-32 messenger RNAs were visualized using alkaline phosphatase-labelled oligonucleotides whilst sites of substance P and proneurotensin messenger RNA expression were detected using (35S)-labelled oligos. Cellular sites of enkephalin and dopamine and adenylate cyclase phosphoprotein-32 gene expression were identified microscopically by the concentration of purple alkaline phosphatase reaction product within the cell cytoplasm, whereas sites of substance P and proneurotensin gene expression were identified by the dense clustering of silver grains overlying cells. An intense hybridization signal was detected for all three neuropeptide messenger RNAs in the striatum, the nucleus accumbens and septum. Dopamine and adenylate cyclase phosphoprotein-32 messenger RNA was detected within the neostriatum but not within the septum. In all forebrain regions examined, with the exception of the islands of Calleja, the cellular expression of enkephalin messenger RNA and substance P messenger RNA was discordant; the two neuropeptide messenger RNAs were detected essentially in different cells, although in the striatum and nucleus accumbens occasional isolated cells were detected which contained both hybridization signals; dense clusters of silver grains overlay alkaline phosphatase-positive cells, demonstrating clearly that these dual-labelled cells expressed both messenger RNAs. By contrast, the hybridization signals for proneurotensin and enkephalin, and proneurotensin and dopamine and adenylate cyclase phosphoprotein-32 were generally coincident, at least within the neostriatum; most proneurotensin messenger RNA-positive cells expressed enkephalin messenger RNA and were also positive for dopamine and adenylate cyclase phosphoprotein-32 messenger RNA. However, occasional proneurotensin messenger RNA-positive striatal cells were identified that were single-labelled and did not express enkephalin messenger RNA. Within the septal nucleus, enkephalin messenger RNA and substance P messenger RNA were expressed essentially within segregated cell populations. These studies illustrate further the utility of co-expression techniques for investigating the chemical phenotype of cells within the CNS and demonstrate that the distribution of neuropeptide co-expressing cells is different within different brain regions. That several populations of proneurotensin messenger RNA-positive striatal cells may exist, of which one population is sensitive to haloperidol, co-expresses enkephalin messenger RNA and is positive for dopamine and adenylate cyclase phosphoprotein-32 messenger RNA may be of some significance in neuropsychiatric/neurological disorders given that the translated peptide, neurotensin, is known to influence and interact closely with the dopamine systems.
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PMID:Phenotypic characterization of neurotensin messenger RNA-expressing cells in the neuroleptic-treated rat striatum: a detailed cellular co-expression study. 913 49

Recent advances in neural mechanisms of taste are reviewed with special reference to neuroactive substances. In the first section, taste transduction mechanisms of basic tastes are explained in two groups, whether taste stimuli directly activate ion channels in the taste cell membrane or they bind to cell surface receptors coupled to intracellular signaling pathways. In the second section, putative transmitters and modulators from taste cells to afferent nerves are summarized. The candidates include acetylcholine, catecholamines, serotonin, amino acids and peptides. Studies favor serotonin as a possible neuromodulator in the taste bud. In the third section, the role of neuroactive substances in the central gustatory pathways is introduced. Excitatory and inhibitory amino acids (e.g., glutamate and GABA) and peptides (substance P and calcitonin gene-related peptide) are proved to play roles in transmission of taste information in both the brainstem relay and cortical gustatory area. In the fourth section, conditioned taste aversion is introduced as a model to study gustatory learning and memory. Pharmacobehavioral studies to examine the effects of glutamate receptor antagonists and protein kinase C inhibitors on the formation of conditioned taste aversion show that both glutamate and protein kinase C in the amygdala and cortical gustatory area play essential roles in taste aversion learning. Recent molecular and genetic approaches to disclose biological mechanisms of gustatory learning are also introduced. In the last section, behavioral and pharmacological approaches to elucidate palatability, taste pleasure, are described. Dopamine, benzodiazepine derivatives and opioid substances may play some roles in evaluation of palatability and motivation to ingest palatable edibles.
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PMID:Roles of chemical mediators in the taste system. 962 13

Dopamine and serotonin neurotransmission regulate striatal preprotachykinin messenger RNA levels. In the present study, we investigated serotonin 2A/2C receptor-mediated regulation of preprotachykinin messenger RNA expression in the rat striatum after adult dopamine depletion produced with 6-hydroxydopamine. Significant reductions (46-61% of control values) in preprotachykinin messenger RNA levels were detected by in situ hybridization in rostral, central and caudal regions of the striatum after >85% dopamine depletion. Repeated administration of the specific serotonin2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide, to dopamine-depleted rats completely reversed the reduction in preprotachykinin messenger RNA levels in rostral, central and dorsal-caudal striatal regions. In unlesioned (vehicle-injected) control animals, repeated administration of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide did not affect preprotachykinin messenger RNA expression in rostral, central and ventral-caudal striatal regions, but decreased preprotachykinin messenger RNA levels in the dorsal-caudal striatal subregion. In addition, serotonin turnover in the dopamine-depleted rostral striatum was significantly increased by 35-45% which is consistent with serotonin hyperinnervation after 6-hydroxydopamine lesions. These data show that the decrease in striatal preprotachykinin messenger RNA after dopamine depletion can be normalized with repeated serotonin2A/2C receptor stimulation. We hypothesize that this serotonin2A/2C receptor regulation of preprotachykinin messenger RNA expression after 6-hydroxydopamine is a consequence of serotonin hyperinnervation, which may include increased striatal serotonin2A/2C receptors, induced by dopamine depletion. We also propose that the serotonin system could be pharmacologically targeted to restore the direct striatal tachykinin pathway in Parkinson's disease.
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PMID:Serotonin-2 receptor stimulation normalizes striatal preprotachykinin messenger RNA in an animal model of Parkinson's disease. 1047 49

We investigated the effects of a schizophrenomimetic drug, phencyclidine (PCP), on substance P (SP) contents in the discrete rat brain areas using an enzyme-immunoassay for SP. The acute intraperitoneal (i.p.) administration of PCP (10 mg/kg), which is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type glutamate receptor and a dopamine uptake inhibitor, reduced the concentration of the peptide in the prefrontal cortex, limbic forebrain, striatum, and substantia nigra, but not in the ventral tegmental area, at 60 or 120 min postinjection. A selective noncompetitive NMDA antagonist, dizocilpine hydrogen maleate ((+)-MK-801) (1 mg/kg, i.p.), also caused a decrease in the SP content in the prefrontal cortex and limbic forebrain but failed to alter the content in the other areas studied 30 min thereafter. Dopamine agonists, methamphetamine (4.8 mg/kg, i.p.) and apomorphine (4.4 mg/kg, i.p.), diminished the SP contents in the striatum and substantia nigra 60 min after their injection without effects in the prefrontal cortex, limbic forebrain, and ventral tegmental area. Furthermore, pretreatment with haloperidol (1 mg/kg, i.p.), a D2 preferable dopamine receptor antagonist and a typical antipsychotic, blocked the ability of PCP to decrease the SP concentrations in the substantia nigra but not in the prefrontal cortex. PCP, therefore, might diminish the SP levels by NMDA receptor-mediated and dopamine-independent mechanisms in the prefrontal cortex and limbic forebrain, but by NMDA receptor-independent and dopamine-dependent mechanisms in the striatum and substantia nigra. The haloperidol-insensitive reduction of the frontal SP could be involved in certain neuroleptic-resistant symptoms of PCP-treated animals, PCP psychosis, or schizophrenia.
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PMID:Differential effects of haloperidol on phencyclidine-induced reduction in substance P contents in rat brain regions. 1065 39

Most studies oriented toward examining mechanisms increasing carotid body (CB) sensitivity to hypoxia during ventilatory acclimatization (VAH) have focussed on the role of known neuromodulators of CB function. Two general categories of the neuromodulatory agents studied most extensively could be considered: those thought to be primarily inhibitory to CB function: dopamine, norepinephrine, nitric oxide and those thought to be primarily excitatory: substance P, endothelin. There is evidence that these putative inhibitory agents are up-regulated in the first weeks of chronic hypoxia and that substance P is down-regulated. All these changes would favor a decrease in CB sensitivity to hypoxia. There are data suggesting that CB endothelin activity is up-regulated in rats subjected to chronic hypoxia, a direction suggesting increased CB sensitivity to hypoxia. Dopamine may have an excitatory as well as an inhibitory role on the CB, but there is not yet evidence to indicate that an excitatory role for DA exists in chronic hypoxia. Ion channel studies of type I CB cells suggest increased excitability after prolonged hypoxia. The role of excitatory CB nicotinic receptors and putative serotonin type 3 receptors should be examined further for their potential role in VAH. It is suggested that a balance of excitatory and inhibitory modulation is responsible for increased CB sensitivity to hypoxia during VAH.
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PMID:Carotid body mechanisms in acclimatization to hypoxia. 1096 78

Dopamine (DA) depletion in neonatal rodents results in depressed tachykinin and elevated enkephalin gene expression in the adult striatum (STR). Concurrently, serotonin (5-HT) fibers sprout to hyperinnervate the DA-depleted anterior striatum (A-STR). The present study was designed to determine if increased 5-HT release from sprouted terminals influences dysregulated preprotachykinin (PPT) and preproenkephalin (PPE) mRNA expression in the DA-depleted STR. Three-day-old Sprague-Dawley rat pups received bilateral intracerebroventricular injections of vehicle or the DA neurotoxin 6-hydroxydopamine (6-OHDA, 100 microg). Two months later, rats received a single intraperitoneal injection of vehicle or the acute 5-HT releasing agent p-chloroamphetamine (PCA; 10 mg/kg). Rats were killed 4 h later and striata processed for monoamine content by HPLC-ED and mRNA expression by in situ hybridization within specific subregions of the A-STR and posterior striatum (P-STR). 6-OHDA treatment severely (>98%) reduced striatal DA levels, while 5-HT content in the A-STR was significantly elevated (doubled), indicative of 5-HT hyperinnervation. Following 6-OHDA, PPT mRNA levels were depressed 60-66% across three subregions of the A-STR and 52-59% across two subregions of the P-STR, while PPE mRNA expression was elevated in both the A-STR (50-62%) and P-STR (55-82%). PCA normalized PPT mRNA levels in all regions of the DA-depleted A-STR and P-STR, yet did not alter PPE levels in either dorsal central or medial regions from 6-OHDA alone, but reduced PPE to control levels in the dorsal lateral A-STR. These data indicate that increased 5-HT neurotransmission, following neonatal 6-OHDA treatment, primarily influences PPT-containing neurons of the direct striatal output pathway.
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PMID:Stimulated serotonin release from hyperinnervated terminals subsequent to neonatal dopamine depletion regulates striatal tachykinin, but not enkephalin gene expression. 1100 Apr 80

The neural control of the subcommissural organ (SCO) has been partially characterized. The best known input is an important serotonergic innervation in the SCO of several mammals. In the rat, this innervation comes from raphe nuclei and appears to exert an inhibitory effect on the SCO activity. A GABAergic innervation has also been shown in the SCO of the rat and frog Rana perezi. In the rat, GABA and the enzyme glutamate decarboxylase are involved in the SCO innervation. GABA is taken up by some secretory ependymocytes and nerve terminals, coexisting with serotonin in a population of synaptic terminals. Dopamine, noradrenaline, and different neuropeptides such as LH-RH, vasopressin, vasotocin, oxytocin, mesotocin, substance P, alpha-neoendorphin, and galanin are also involved in SCO innervation. In the bovine SCO, an important number of fibers containing tyrosine hydroxylase are present, indicating that in this species dopamine and/or noradrenaline-containing fibers are an important neural input. In Rana perezi, a GABAergic innervation of pineal origin could explain the influence of light on the SCO secretory activity in frogs. A general conclusion is that the SCO cells receive neural inputs from different neurotransmitter systems. In addition, the possibility that neurotransmitters and neuropeptides present in the cerebrospinal fluid may also affect the SCO activity, is discussed.
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PMID:Neural input and neural control of the subcommissural organ. 1124 62

Spinal locomotor networks in the lamprey are modulated by tachykinin neuropeptides. A single 10 min application of the tachykinin substance P evokes a short-term ( approximately 1 hr) presynaptic facilitation of glutamate release and the postsynaptic potentiation of NMDA responses. The latter effect induces a long-term (>24 hr) protein synthesis-dependent increase in the frequency of network activity. Tachykinins are contained in a ventromedial spinal plexus into which the medial dendrites of network neurons project. Neurons in this plexus also contain colocalized dopamine and 5-HT. Here, dynamic plasticity evoked by modulator interactions has been examined by investigating the effects of 5-HT and dopamine on specific cellular, synaptic, and network effects of substance P. Preapplied 5-HT blocked the substance P-mediated increase in the network burst frequency and the potentiation of NMDA-evoked cellular responses that underlies its induction. 5-HT also blocked the presynaptic facilitation of glutamatergic synaptic transmission by substance P. The presynaptic, but not postsynaptic, effect of 5-HT was reduced by the protein phosphatase 2B inhibitor cypermethrin. Dopamine did not directly modulate the effects of substance P. However, it reduced the presynaptic interactive effect of 5-HT and thus gated the presynaptic potentiation of glutamatergic inputs by substance P. However, the substance P-mediated potentiation of NMDA responses was not gated by dopamine, and thus the long-term network modulation was not induced. Neuromodulator effects and their interactions can thus be modulated. By selecting components from the modulatory repertoire of substance P, these interactions evoke dynamic changes in short- and long-term synaptic and network plasticity.
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PMID:Gating and braking of short- and long-term modulatory effects by interactions between colocalized neuromodulators. 1148 21


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