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)

Previous studies have shown that the striatum provides synaptic inputs to the globus pallidus and entopeduncular nucleus in which GABA is co-localized with the peptides enkephalin and substance P. The aim of this study in the rat was to determine whether the striatal projections also make synaptic contact with the cholinergic neurons of the nucleus basalis, which lie near to the pallidal areas in the rat brain. The anterograde tracer biocytin was injected into different parts of the striatum, and brain sections were stained for biocytin and choline acetyltransferase immunoreactivity by using a dual colour method. Terminals labelled with biocytin by anterograde transport and which made synaptic contact with choline acetyltransferase-positive soma and dendrites were identified by light-electron microscopic correlation methods. In the cases where the biocytin injections had been made in the dorsal or lateral striatum, biocytin-labelled terminals made synaptic contact with cholinergic cells in the region between the main termination zones in the globus pallidus and the entopeduncular nucleus. In the cases where the injections had been made in the ventromedial and posterior striatum, there was greater overlap between choline acetyltransferase-positive structures and biocytin-labelled terminals in the main termination zones in the globus pallidus or entopeduncular nucleus, but relatively few of these terminals made synaptic contacts on to the cholinergic neurons. The results therefore indicate that the cholinergic nucleus basalis cells receive a relatively sparse synaptic input from all parts of the striatum. It has recently been shown that the cholinergic cells of the nucleus basalis selectively express high levels of substance P and opioid receptor messenger RNAs, while the non-cholinergic pallidal cells have much higher levels of GABA(A) receptor subunit messenger RNAs. It is concluded that the cholinergic neurons of the nucleus basalis in the rat may be selectively responsive to the peptidergic components of the striatal outputs, and that they are most likely to be influenced by both the limbic and sensorimotor parts of the striatum.
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PMID:The projection from the striatum to the nucleus basalis in the rat: an electron microscopic study. 917 63

1. The pattern of responses of longitudinally oriented guinea pig ileum organ bath preparations was studied during short- (1-5 sec) or long-lasting (20 sec) electrical field stimulation (EFS, 0.8 msec, 40 V, 1-20 Hz). 2. In the presence of phentolamine (5 microM), propranolol (5 microM), and atropine (3 microM), the EFS elicited nonadrenergic, noncholinergic (NANC), tetrodotoxin (0.3 microM)-sensitive responses. 3. The 1-sec EFS evoked relaxation. The response to 5-sec EFS consisted of relaxation followed by twitch, whereas relaxation, twitch and tonic contraction characterized the NANC response to 20-sec EFS. The maximum relaxation was observed at 10-Hz short- or long-lasting EFS. 4. Both N-G-nitro-L-arginine (L-NNA, 0.1-0.5 mM) and apamin (1-5 microM) concentration dependently inhibited the relaxation of the NANC response to 10-Hz 20-sec EFS. During L-NNA treatment, the twitch and the tonic contractions were increased. The inhibitory effect of L-NNA was reversed by L-arginine (0.1-0.5 mM) but not by D-arginine. Sodium nitroprusside (1-10 microM) was without effect. 5. AP 13.2 ACOH (0.1 microM), a blocker of Substance P receptors, inhibited the twitch and the tonic contractions. The contractions were decreased after desensitization of purinoceptors by ATP and in the presence of the GABA(A) receptor antagonist bicuculline (30 microM). 6. Depending on the EFS duration, a subsequent occurrence of relaxation and contractions characterized the NANC responses. It seems that relaxation is mediated by nitric oxide whereas Substance P and ATP are involved in the maintenance of the twitch and the tonic contractions. Nitric oxide appears to exert an inhibitory effect on the excitatory transmitters, whereas purinergic mechanism(s) could modulate the nitric oxide-dependent relaxation.
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PMID:Pattern of nonadrenergic, noncholinergic responses during short- or long-lasting electrical stimulation in guinea-pig ileum. 925 5

To better understand the organization and evolution of the basal ganglia of vertebrates, in the present study we have analyzed the chemoarchitecture and the cortical input to the nucleus accumbens in the lacertid lizard Psammodromus algirus. The nucleus accumbens contains many gamma-aminobutyric acid (GABA)-positive neurons and calbindin-positive neurons, the majority of which may be spiny projection neurons, and a few dispersed neuropeptide Y-positive neurons that likely represent aspiny interneurons. The nucleus accumbens contains two chemoarchitectonically different fields: a rostromedial field that stains heavily for substance P, dopamine, GABA(A) receptor, and a caudolateral field that stains only lightly to moderately for them, appearing more similar to the adjacent striatum. Injections of biotinylated dextran amine were placed in either the medial, dorsomedial, or dorsal cortices of Psammodromus. The medial and the dorsal cortices project heavily to the rostromedial field of the accumbens, whereas they project lightly to moderately to the caudolateral field. Cortical terminals make asymmetric, presumably excitatory, synaptic contacts with distal dendrites and the head of spines. Our results indicate that the hippocampal-like projection to the nucleus accumbens is similar between mammals and reptiles in that cortical terminals make mainly excitatory synapses on spiny, putatively projection neurons. However, our results and results from previous investigations indicate that important differences exist between the nucleus accumbens of mammals and reptiles regarding local modulatory interactions between cortical, dopaminergic, and cholinergic elements, which suggest that the reptilian nucleus accumbens may be as a whole comparable to the shell of the mammalian nucleus accumbens.
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PMID:Nucleus accumbens in the lizard Psammodromus algirus: chemoarchitecture and cortical afferent connections. 1002 93

The purpose of this study was to investigate whether GABA(A) receptors in the dorsal striatum regulate basal or stimulant-induced behaviors. Correspondingly, the question of possible GABA(A) receptor control of neuropeptide mRNA expression in nigrostriatal neurons was addressed. The GABA(A) receptor antagonist, bicuculline, was unilaterally or bilaterally microinjected into the dorsal striatum of rats in a series of 3 studies. In the first study, unilateral administration of 10-50 ng/microliter of bicuculline did not alter behavior. However, 250 ng/microliter bicuculline produced motor dyskinesias and/or seizures. In the second study, 100 ng/microliter bicuculline administered unilaterally prior to saline or amphetamine treatment, produced mild twitching in 61% of rats but did not affect amphetamine (2.5 mg/kg, i.p.)-induced behavioral activity, specifically rearing and sniffing. In the third study, 75 ng/microliter of bicuculline was administered unilaterally or bilaterally into the striatum in two separate experiments. Administration of bicuculline either unilaterally or bilaterally produced mild transient twitching of the forelimbs but did not affect behaviors induced by the selective D(1) receptor agonist SKF-82958 (0.5 mg/kg, s.c.). Three hours after unilateral bicuculline administration, the brains were removed and processed for quantitative in situ hybridization. Bicuculline did not significantly affect the basal or SKF-82958-induced increase in preprodynorphin or substance P mRNA expression in striatonigral neurons on the side of injection. These data suggest that blockade of GABA(A) receptors in the dorsal striatum does not affect dopamine agonist-stimulated behaviors or neuropeptide mRNA expression in striatonigral neurons in the rat striatum.
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PMID:The role of dorsal striatal GABA(A) receptors in dopamine agonist-induced behavior and neuropeptide gene expression. 1041 9

In order to investigate the sequence and pattern of neurodegeneration in Huntington's disease, the distribution and density of cannabinoid CB(1), dopamine D(1) and D(2), adenosine A(2a) and GABA(A) receptor changes were studied in the basal ganglia in early (grade 0), intermediate (grades 1, 2) and advanced (grade 3) neuropathological grades of Huntington's disease. The results showed a sequential pattern of receptor changes in the basal ganglia with increasing neuropathological grades of Huntington's disease. First, the very early stages of the disease (grade 0) were characterized by a major loss of cannabinoid CB(1), dopamine D(2) and adenosine A(2a) receptor binding in the caudate nucleus, putamen and globus pallidus externus and an increase in GABA(A) receptor binding in the globus pallidus externus. Second, intermediate neuropathological grades (grades 1, 2) showed a further marked decrease of CB(1) receptor binding in the caudate nucleus and putamen; this was associated with a loss of D(1) receptors in the caudate nucleus and putamen and a loss of both CB(1) and D(1) receptors in the substantia nigra. Finally, advanced grades of Huntington's disease showed an almost total loss of CB(1) receptors and the further depletion of D(1) receptors in the caudate nucleus, putamen and globus pallidus internus, and an increase in GABA(A) receptor binding in the globus pallidus internus. These findings suggest that there is a sequential but overlapping pattern of neurodegeneration of GABAergic striatal efferent projection neurons in increasing neuropathological grades of Huntington's disease. First, GABA/enkephalin striatopallidal neurons projecting to the globus pallidus externus are affected in the very early grades of the disease. Second, GABA/substance P striatonigral neurons projecting to the substantia nigra are involved at intermediate neuropathological grades. Finally, GABA/substance P striatopallidal neurons projecting to the globus pallidus internus are affected in the late grades of the disease. In addition, the finding that cannabinoid receptors are dramatically reduced in all regions of the basal ganglia in advance of other receptor changes in Huntington's disease suggests a possible role for cannabinoids in the progression of neurodegeneration in Huntington's disease.
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PMID:The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. 1082 33

Internalization of spinal cord neurokinin-1 receptors following noxious stimulation provides a reliable measure of tachykinin signaling. In the present study, we examined the contribution of GABAergic mechanisms to the control of nociceptor processing involving tachykinins. Spinal administration of the GABA(B) receptor agonist R(+)-baclofen in the rat, at antinociceptive doses, significantly reduced the magnitude of neurokinin-1 receptor internalization in neurons of lamina I in response to acute noxious mechanical or thermal stimulation. By contrast, administration of even high doses of the GABA(A) receptor agonists, muscimol or isoguvacine, were without effect. CGP55845, a selective GABA(B) receptor antagonist, completely blocked the effects of baclofen, but failed to increase the incidence of internalization when administered alone. These results provide evidence for a presynaptic control of nociceptive primary afferent neurons by GABA(B) but not GABA(A) receptors in the superficial laminae of the spinal cord, limiting tachykinin release. Because CGP5584 alone did not increase the magnitude of neurokinin-1 receptor internalization observed following noxious stimulation, there appears to be little endogenous activation of GABA(B) receptors on tachykinin-releasing nociceptors under acute stimulus conditions. The contribution of pre- and postsynaptic regulatory mechanisms to GABA(B) receptor-mediated antinociception was also investigated by comparing the effect of baclofen on Fos expression evoked by noxious stimulation to that induced by intrathecal injection of substance P. In both instances, baclofen reduced Fos expression not only in neurons that express the neurokinin-1 receptor, but also in neurons that do not. We conclude that baclofen acts at presynaptic sites to reduce transmitter release from small-diameter nociceptive afferents. Presynaptic actions on non-tachykinin-containing nociceptors could similarly account for the reduction by baclofen of noxious stimulus-induced Fos expression in neurokinin-1 receptor-negative neurons. However, the inhibition of Fos expression induced by exogenous substance P indicates that actions at sites postsynaptic to tachykinin- and/or non-tachykinin-containing primary afferent terminals must also contribute to the antinociceptive actions of GABA(B) receptor agonists.
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PMID:Presynaptic regulation of spinal cord tachykinin signaling via GABA(B) but not GABA(A) receptor activation. 1127 91

1 The activation of tachykinin NK(1) receptors in the rat spinal cord produced a transient drop in arterial blood pressure followed by a more prolonged pressor effect which is mediated by the stimulation of the sympatho-adrenal system. This study aims at characterizing the spinal mechanism of that initial hypotension occurring in awake unrestrained rats. 2 The initial hypotension (-18+/-2.0 mmHg at 1 min) and the tachycardia (110+/-10 b.p.m.) produced by the intrathecal (i.t.) injection of the stable NK(1) receptor agonist [Sar(9), Met(O(2))(11)]-SP (Sar9, 0.65 nmol) at T-9 spinal cord level was inhibited by the prior injection of 65 nmol LY306740 or LY303870 (NK(1) receptor antagonists). No inhibition was seen when a similar dose of antagonists was given intravenously. 3 The prior i.t. injection of the GABA(B) receptor antagonist CGP52432 (100 nmol) reduced the hypotension evoked by Sar9 (0.65 nmol) and by the GABA(B) receptor agonist baclofen (100 nmol). The GABA(A) receptor antagonist bicuculline (25 nmol, i.t.) was without effect against Sar9, and the GABA(A) agonist muscimol (100 nmol, i.t.) had no cardiovascular effect. 4 The putative involvement of other mediators (dopamine, serotonine, glycine and glutamate) in Sar9-induced hypotension was made unlikely on the basis of various pharmacological treatments. Thus data, suggest that the transient hypotension which occurs upon the activation of NK(1) receptors in the spinal cord is due to the release of GABA which in turn activates GABA(B) receptors to inhibit sympathetic pre-ganglionic fibres. This mechanism may have a physiological significance in the spinal reflex autonomic control of arterial blood pressure.
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PMID:Evidence for a GABA(B) receptor component in the spinal action of Substance P (SP) on arterial blood pressure in the awake rat. 1216 50

Neurochemical changes were examined in dopamine D1 receptor knockout (D1(-/-)), dopamine D3 receptor knockout (D3(-/-)) and dopamine D1/D3 receptor double knockout (D1(-/-)D3(-/-)) mice. The level of dopamine D1- and D2-like receptors and gamma-aminobutyric acid (GABA(A)) receptor was assessed by ligand autoradiography and dopamine D1- and D2 receptor, enkephalin, dynorphin and substance P transcripts measured by in situ hybridization. D1(-/-) mice had normal GABA(A) receptor levels, reduced dynorphin and substance P, and increased enkephalin mRNA and dopamine D2-like binding. D1(-/-)D3(-/-) mice evidenced decreased dynorphin and substance P but normal enkephalin expression, whereas dopamine D2-like and GABA(A) receptor binding were increased. Major changes occur in substance P and dynorphin expression in D1(-/-) mice and these changes are unaffected by loss of dopamine D3 receptors. Upregulated dopamine D2-like binding and enkephalin in D1(-/-) mice may be due to decreased dopamine turnover. Upregulated enkephalin in D1(-/-) mice is dependent on functional dopamine D3 receptors.
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PMID:Neurochemical changes in dopamine D1, D3 and D1/D3 receptor knockout mice. 1286 Apr 71

Tachykinin (TK; including substance P (SP), neurokinin A (NKA) and neurokinin B (NKB))-induced currents (I(TK)s) were studied in freshly isolated rat dorsal root ganglion (DRG) neurons using whole-cell patch clamp recording and repatch techniques. All the three I(TK)s manifested features of fast activating kinetics, such as short latency and fast tau(on) and tau(off), and very slow desensitization. The concentration-response relationships for TKs show: (1). compared with the concentration-response curve for NKA, the curve for NKB shifted upwards, while that for SP shifted downwards; (2). the EC(50) values for NKB-, NKA- and SP-activated currents were very close to each other. The I-V curves for the three TKs were basically linear and arrayed in the order of NKB>NKA>SP; the reversal potentials for the three I(TK)s were all around +15 mV. Replacement of NaCl in the external solution by equimolar N-methyl-D-glucamine (NMDG) attenuated both NKA- and NKB-activated currents markedly, as it was the case with SP-activated current caused by the opening of Na(+) preferring non-selective cation channels observed in our previous work. All the three TKs proved to inhibit coexistent GABA(A) receptor-mediated current (I(GABA)); this effect was removed by intracellular dialysis of GDP-beta-S or H-7. However, these drugs did not block the SP-, NKA- and NKB-activated currents at all, which indicated that I(TK)s were G-protein independent. In short, the responses of rat DRG neurons to SP, NKA and NKB were similar in essence, although the amplitudes of currents induced by the same concentration of the three TKs were different. Taking the results of this study and our previous studies together, we hypothesized that SP, NKA and NKB may induce inward currents through undiscovered channels that are associated with tachykinins receptors (NK1R, NK2R, NK3R, which have already been cloned), but independent of G-protein coupling and remains to be further investigated.
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PMID:Similarities of SP-, NKA- and NKB-induced currents in rat dorsal root ganglion neurons. 1457 72

The modulation by substance P of gamma-aminobutyric acid (GABA)- and 5-hydroxytryptamine (5-HT)-activated currents (I(GABA) and I(5-HT)) was studied by using patch-clamp technique in rat trigeminal ganglion (TG) neurons. The majority of neurons examined responded to GABA and 5-HT with inward currents in the same cells (63.8%, 30/47). In 22 out of 30 neurons sensitive to both GABA and 5-HT, pretreatment with substance P (SP, 0.01 micromol/L) suppressed I(GABA) by (35.7 +/-6.1)% and enhanced I(5-HT) by (65.2 +/- 8.7)%. GR 82334, a potent and specific antagonist of NK1 tachykinin receptor, reversibly blocked the modulatory effects of SP. The SP modulation on I(GABA) and I(5-HT) was also abolished by intracellular dialysis of GDP-beta-S, a non-hydrolyzable GDP analog, or GF 109203X, a selective protein kinase C inhibitor. These results suggest that SP exerts opposite modulatory actions on GABA(A) receptor and 5-HT3 receptor activity of the same primary sensory neuron via the same intracellular signal transduction pathway.
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PMID:Opposite modulatory effects of substance P on GABA-and 5-HT-activated currents in the same sensory neurons. 1561 18


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