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)

It has been hypothesized that dopamine(D1) and serotonin(2) receptors become sensitized to agonist-mediated regulation of gene expression following loss of dopaminergic innervation to the striatum. We have previously demonstrated that the combined administration of dopamine(D1) and serotonin(2) receptor agonists to dopamine-depleted adult rats induced preprotachykinin mRNA expression within the periventricular rostral striatum to levels which were significantly different than what could be elicited by either agonist alone. In the present study, we have determined that this phenomenon is revealed only after dopamine depletion. In addition, it is targeted primarily to tachykinin producing neurons of the dorsomedial striatum and is dependent on both dopamine(D1) and serotonin(2) receptor activation. Preprotachykinin mRNA levels in the intact striatum were unaltered 4 h following an i.p. injection of either SKF-38393 (1 mg/kg, dopamine(D1) partial agonist) or (+/-)-1-(4-Iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI 1 mg/kg, serotonin(2) agonist). However, the combined application of both agonists increased (+44%) preprotachykinin message levels, but these changes were restricted to the dorsomedial striatum. In adult animals depleted of dopamine as neonates, striatal preprotachykinin mRNA expression was reduced by approximately 50%. From this lowered level of basal expression, DOI or SKF-38393 raised preprotachykinin mRNA levels within the dorsomedial, but not the dorsolateral striatum. Furthermore, co-stimulation of dopamine(D1) and serotonin(2) receptors produced a nearly four-fold induction of preprotachykinin message levels in the dorsomedial striatum that was significantly greater than either agonist alone. Application of both agonists also elevated preprotachykinin mRNA expression within the dorsolateral striatum, but to a lesser extent. All increases in preprotachykinin mRNA resulting from co-application of SKF-38393 and DOI were prevented by pretreatment with either SCH-23390 (1 mg/kg, dopamine(D1) antagonist) or ritanserin (1 mg/kg, serotonin(2) antagonist). Alternately, preproenkephalin mRNA expression was unaffected by dopamine(D1) receptor stimulation, but was slightly elevated by DOI or both agonists together (42-58%) in intact animals. However, neither agonist treatment in this experiment significantly altered preproenkephalin mRNA expression in the dopamine-depleted striatum which was elevated in response to dopamine lesion alone. Dopamine depletion appears to promote a synergistic interaction between dopamine(D1) and serotonin(2) receptors that leads to enhanced expression of striatal preprotachykinin mRNA levels. The localization of this phenomenon to tachykinin neurons of the direct striatonigral pathway specifically within the dorsomedial regions of the rostral striatum may be relevant to the problem of dyskinetic behaviors which arise during the pharmacological treatment of movement disorders.
 ...
PMID:Neonatal dopamine depletion reveals a synergistic mechanism of mRNA regulation that is mediated by dopamine(D1) and serotonin(2) receptors and is targeted to tachykinin neurons of the dorsomedial striatum. 1151 32

10.1152/jn.00224.2002. Dopamine (DA) modulates the cardiorespiratory reflex by peripheral and central mechanisms. The aim of this study was to examine the role of DA in synaptic transmission of the nucleus tractus solitarius (NTS), the major integration site for cardiopulmonary reflexes. To examine DA's role, we used whole cell, voltage-clamp recordings in a rat horizontal brain stem slice. Solitary tract stimulation evoked excitatory postsynaptic currents (EPSCs) that were reduced to 70 +/- 5% of control by DA (100 microM). The reduction in EPSCs by DA was accompanied by a decrease in the paired pulse depression ratio with little or no change in input resistance or EPSC decay, suggesting a presynaptic mechanism. The D1-like agonist SKF 38393 Br (30 microM) did not alter EPSC amplitude, whereas the D2-like agonist, quinpirole HCl (30 microM), depressed EPSCs to 73 +/- 4% of control. The D2-like receptor antagonist, sulpiride (20 microM), abolished DA modulation of EPSCs. Most importantly, sulpiride alone increased EPSCs to 131 +/- 10% of control, suggesting a tonic D2-like modulation of synaptic transmission in the NTS. Examination of spontaneous EPSCs revealed DA reversibly decreased the frequency of events from 9.4 +/- 2.2 to 6.2 +/- 1.4 Hz. Sulpiride, however, did not alter spontaneous events. Immunohistochemistry of NTS slices demonstrated that D2 receptors colocalized with synaptophysin and substance P, confirming a presynaptic distribution. D2 receptors also localized to cultured petrosal neurons, the soma of presynaptic afferent fibers. In the petrosal neurons, D2 was found in cells that were TH-immunopositive, suggesting they were chemoreceptor afferent fibers. These results demonstrate that DA tonically modulates synaptic activity between afferent sensory fibers and secondary relay neurons in the NTS via a presynaptic D2-like mechanism.
 ...
PMID:Dopamine modulates synaptic transmission in the nucleus of the solitary tract. 1242 8

We have recently examined the status of the endocannabinoid transmission in the basal ganglia in Huntington's disease (HD) using a rat model generated by bilateral intrastriatal injections of 3-nitropropionic acid (3-NP). In these previous studies, we focused on the early phase of hyperactivity that occurs 1-2 weeks after the lesion, comparable to early grades of the human disease, while in the present study, we wanted to explore the late akinetic phase observed 3-4 weeks after the lesion (similar to advanced grades). First, we confirmed that 3-NP-lesioned rats exhibited a marked akinesia tested at 4 weeks post-lesion. We observed a marked reduction in ambulatory and exploratory activities and a trend towards a decrease in stereotypies, paralleled by a strong increase in the time spent in inactivity. There was also a profound reduction in GABA contents and glutamic acid decarboxylase activity, particularly in the caudate-putamen and the globus pallidus. Dopamine and DOPAC contents, as well as the activity of tyrosine hydroxylase, were also reduced, particularly in the caudate-putamen. mRNA levels for neuronal-specific enolase, proenkephalin and substance P were also dramatically reduced in the caudate-putamen, thus indicating a death of both the direct (striatonigral) and the indirect (striatopallidal) GABAergic projection pathways, which corresponded with a marked loss of CB(1) receptor-mRNA levels observed in both parts, lateral and medial, of the caudate-putamen. However, losses of CB(1) receptor binding were confined to the globus pallidus and the caudate-putamen, whereas there were no changes in the substantia nigra and the entopeduncular nucleus. Finally, we failed to reduce the marked akinesia found in these animals by administering SR141716A, a selective antagonist of CB(1) receptors, which had exhibited hyperlocomotor effects in previous studies with naive animals. In summary, behavioral and biochemical changes observed in rats intrastriatally lesioned with 3- NP were compatible with a profound degeneration of striatal efferent GABAergic neurons, similar to those occurring in advances stages of the human disease. As expected, a loss of CB(1) receptors was evident in the basal ganglia of these rats during the late akinetic stage of the disease. Further studies should demonstrate whether these receptors might be a target for a new therapy in HD, a disease with a poor pharmacological outcome.
 ...
PMID:Loss of cannabinoid CB(1) receptors in the basal ganglia in the late akinetic phase of rats with experimental Huntington's disease. 1270 98

Dopamine (DA) and glutamate neurotransmission is thought to be critical for psychostimulant drugs to induce immediate early genes (IEGs) in the caudate-putamen (CPu). We report here, however, that the ability of DA and glutamate NMDA receptor antagonists to attenuate amphetamine-evoked c-fos mRNA expression in the CPu depends on environmental context. When given in the home cage, amphetamine induced c-fos mRNA expression predominately in preprodynorphin and preprotachykinin mRNA-containing neurons (Dyn-SP+ cells) in the CPu. In this condition, all of the D1R, D2R and NMDAR antagonists tested dose-dependently decreased c-fos expression in Dyn-SP+ cells. When given in a novel environment, amphetamine induced c-fos mRNA in both Dyn-SP+ and preproenkephalin mRNA-containing neurons (Enk+ cells). In this condition, D1R and non-selective NMDAR antagonists dose-dependently decreased c-fos expression in Dyn-SP+ cells, but neither D2R nor NR2B-selective NMDAR antagonists had no effect. Furthermore, amphetamine-evoked c-fos expression in Enk+ cells was most sensitive to DAR and NMDAR antagonism; the lowest dose of every antagonist tested significantly decreased c-fos expression only in these cells. Finally, novelty-stress also induced c-fos expression in both Dyn-SP+ and Enk+ cells, and this was relatively resistant to all but D1R antagonists. We suggest that the mechanism(s) by which amphetamine evokes c-fos expression in the CPu varies depending on the stimulus (amphetamine vs. stress), the striatal cell population engaged (Dyn-SP+ vs. Enk+ cells), and environmental context (home vs. novel cage).
 ...
PMID:Amphetamine-evoked c-fos mRNA expression in the caudate-putamen: the effects of DA and NMDA receptor antagonists vary as a function of neuronal phenotype and environmental context. 1280 22

We investigated the expression of the substance P (SP) receptor (the neurokinin 1 receptor, NK1 receptor) and SP functional effects in developing rabbit retinas. NK1 receptors in adult retinas were in a population of cone bipolar cells and in dopaminergic amacrine cells, as previously described. In contrast, at birth and at postnatal day (PND) 6, NK1 receptors were exclusively expressed by cholinergic amacrine and displaced amacrine cells. NK1 receptor expression in cholinergic cells was still observed at PND10 (eye opening), while at PND21 it was confined to cholinergic cells of the inner nuclear layer. Starting at PND10, NK1 receptors were also in bipolar cells and in dopaminergic amacrine cells. A fully mature NK1 receptor expression pattern was observed at PND35. Dopamine release was assessed in isolated retinas in the presence of SP, the NK1 receptor agonist GR73632 or the NK1 receptor antagonist GR82334. At PND35, extracellular dopamine was significantly increased by 10 microM SP or 0.01-100 microM GR73632, and it was decreased by 0.01-10 microM GR82334. No effects were detected in developing retinas up to PND21. Ca2+ imaging experiments were performed in single cholinergic cells identified by their "starburst" morphology in perinatal retinas. Intracellular Ca2+ levels were significantly increased by 1 microM SP or GR73632. This effect was reversibly inhibited by 1 microM GR82334. These data demonstrate that both NK1 receptor expression and SP physiological actions are developmentally regulated in the retina. SP neurotransmission in the immature retina may subserve developmental events, and SP is likely to represent an important developmental factor for the maturation of retinal neurons and circuitries.
 ...
PMID:Neurokinin 1 receptor expression and substance P physiological actions are developmentally regulated in the rabbit retina. 1496 Mar 47

Dopamine action alters gene regulation in striatal neurons. Methylphenidate increases extracellular levels of dopamine. We investigated the effects of acute methylphenidate treatment on gene expression in the striatum of adult rats. Molecular changes were mapped in 23 striatal sectors mostly defined by their predominant cortical inputs in order to determine the functional domains affected. Acute administration of 5 and 10 mg/kg (i.p.) of methylphenidate produced robust increases in the expression of the transcription factor c-fos and the neuropeptide substance P. Borderline effects were found with 2 mg/kg, but not with 0.5 mg/kg. For 5 mg/kg, c-fos mRNA levels peaked at 40 min and returned to baseline by 3 h after injection, while substance P mRNA levels peaked at 40-60 min and were back near control levels by 24 h. These molecular changes occurred in most sectors of the caudate-putamen, but were maximal in dorsal sectors that receive sensorimotor and medial agranular cortical inputs, on middle to caudal levels. In rostral and ventral striatal sectors, changes in c-fos and substance P expression were weaker or absent. No effects were seen in the nucleus accumbens, with the exception of c-fos induction in the lateral part of the shell. In contrast to c-fos and substance P, acute methylphenidate treatment had minimal effects on the opioid peptides dynorphin and enkephalin. These results demonstrate that acute methylphenidate alters the expression of c-fos and substance P preferentially in the sensorimotor striatum. These molecular changes are similar, but not identical, to those produced by other psychostimulants.
 ...
PMID:Topography of methylphenidate (ritalin)-induced gene regulation in the striatum: differential effects on c-fos, substance P and opioid peptides. 1563 41

Dopamine-induced changes in striatal gene expression are thought to play an important role in drug addiction and compulsive behaviour. In this study we report that dopamine induces the expression of the transcription factor CCAAT/Enhancer Binding Protein beta (C/EBP)-beta in primary cultures of striatal neurones. We identified the preprotachykinin-A (PPT-A) gene coding for substance P and neurokinin-A as a potential target gene of C/EBPbeta. We demonstrated that C/EBPbeta physically interacts with an element of the PPT-A promoter, thereby facilitating substance P precursor gene transcription. The regulation of PPT-A gene by C/EBPbeta could subserve many important physiological processes involving substance P, such as nociception, neurogenic inflammation and addiction. Given that substance P is known to increase dopamine signalling in the striatum and, in turn, dopamine increases substance P expression in medium spiny neurones, our results implicate C/EBPbeta in a positive feedback loop, changes of which might contribute to the development of drug addiction.
 ...
PMID:C/EBPbeta couples dopamine signalling to substance P precursor gene expression in striatal neurones. 1677 29

The vesicular monoamine transporter type 2 (VMAT2) packages pre-synaptic monoamines into vesicles. Previously, we generated mice hypomorphic for the VMAT2 gene (Slc18a2), which results in a approximately 95% reduction in VMAT2 protein, disrupted vesicular storage, severe depletion of striatal dopamine and mice with moderate motor behaviour deficits. Dopamine released from mid-brain dopamine neurons acts on post-synaptic type 1 (D1) and 2 (D2) receptors located on striatal medium spiny neurons to initiate a signalling cascade that leads to altered transcription factor activity, gene expression and neuronal activity. We investigated striatal gene expression changes in VMAT2hypo mice by quantitative real-time PCR and in situ hybridisation. Despite unaltered expression of D1 and D2 dopamine receptors, there were dramatic alterations in striatal mRNAs encoding the neuropeptides substance P, dynorphin, enkephalin and cholecystokinin. The promoters of these genes are regulated by a combination of transcription factors that includes cAMP responsive element binding protein-1 (CREB) and c-Fos. Indeed, the changes in peptide mRNAs were associated with elevated expression of Creb1 and c-Fos. These data indicate that striatal dopamine depletion, as a consequence of deficient vesicular storage in this mouse, triggers a complex program of gene expression, consistent with this mouse being an excellent model of Parkinson's disease.
 ...
PMID:Differential gene expression in the striatum of mice with very low expression of the vesicular monoamine transporter type 2 gene. 1743 7

Neuromodulators can change the output of neural circuits. The crustacean cardiac ganglion (CG) drives the contractions of the heart. The CG is a direct target for neurohormones that are released from the pericardial organs and other neuroendocrine sites. In this study, we have characterized for the first time the physiological actions of the peptides red pigment concentrating hormone (RPCH), Cancer borealis tachykinin-related peptide Ia (CabTRP Ia) and allatostatin III type A (AST-3) on the isolated CG of the crab, Cancer borealis. RPCH and CabTRP Ia excited the CG while AST-3 strongly inhibited its motor output. We also studied the actions of other peptides and small molecule transmitters known to be present in C. borealis. Dopamine, serotonin, proctolin, crustacean cardioactive peptide (CCAP), a number of extended FLRFamide peptides, and cholinergic agonists increased the activity of the CG, GABA inhibited the CG, while other substances had little or no significant effect on the CG motor pattern. These results demonstrate, in one species, that the CG is multiply modulated. We suggest that multiple modulators may be important to regulate and coordinate the activity of the heart and other organs in response to external stimuli or the endogenous physiological state.
 ...
PMID:Multiple modulators act on the cardiac ganglion of the crab, Cancer borealis. 1769 Feb 36

Modulation of neural circuits in the crustacean stomatogastric nervous system (STNS) allows flexibility in the movements of the foregut musculature. The extensive repertoire of such resulting motor patterns in dietary generalists is hypothesized to permit these animals to process varied foods. The foregut and STNS of Pugettia producta are similar to those of other decapods, but its diet is more uniform, consisting primarily of kelp. We investigated the distribution of highly conserved neuromodulators in the stomatogastric ganglion (STG) and neuroendocrine organs of Pugettia, and documented their effects on its pyloric rhythm. Using immunohistochemistry, we found that the distributions of Cancer borealis tachykinin-related peptide I (CabTRP I), crustacean cardioactive peptide (CCAP), proctolin, red pigment concentrating hormone (RPCH) and tyrosine hydroxylase (dopamine) were similar to those of other decapods. For all peptides except proctolin, the isoforms responsible for the immunoreactivity were confirmed by mass spectrometry to be the authentic peptides. Only two modulators had physiological effects on the pyloric circuit similar to those seen in other species. In non-rhythmic preparations, proctolin and the muscarinic acetylcholine agonist oxotremorine consistently initiated a full pyloric rhythm. Dopamine usually activated a pyloric rhythm, but this pattern was highly variable. In only about 25% of preparations, RPCH activated a pyloric rhythm similar to that seen in other species. CCAP and CabTRP I had no effect on the pyloric rhythm. Thus, whereas Pugettia possesses all the neuromodulators investigated, its pyloric rhythm, when compared with other decapods, appears less sensitive to many of them, perhaps because of its limited diet.
 ...
PMID:The pyloric neural circuit of the herbivorous crab Pugettia producta shows limited sensitivity to several neuromodulators that elicit robust effects in more opportunistically feeding decapods. 1842 77


<< Previous 1 2 3 4 5 6 Next >>