Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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

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

The effects of acute and repeated daily cocaine on the levels of mRNA coding for glutamic acid decarboxylase (GAD), preproenkephalin (PPE), preprotachykinin (PPT), and the dopamine D2 receptor were determined in the striatum, nucleus accumbens core and shell areas (NAcore, NAshell), and medial prefrontal cortex. Rats were given repeated saline or cocaine for 6 days. A cocaine challenge administered 24 h later resulted in an augmented locomotor response in daily cocaine-pretreated rats. Six h after the challenge, rats were sacrificed and Northern blot analysis revealed that acute cocaine increased GAD mRNA levels by 44% in the NAshell, while repeated cocaine prevented the acute cocaine-induced increase. These data suggest that cocaine may differentially regulate GABA release at NA core and shell projection fields.
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PMID:Cocaine alters glutamic acid decarboxylase differentially in the nucleus accumbens core and shell. 760 27

Adenosine acts as a neuromodulator through A1 and A2 receptors. The adenosine analogs have been recognized, among other effects, as strong depressors of the locomotor activity by acting on striatal A2 receptors. Moreover, the A2a receptor subtype is exclusively expressed in the striatum. To elucidate at the cellular level the roles of adenosine in the basal ganglia, the anatomical and functional relationships of the A2 receptors with the dopamine D1 and D2 receptors were studied in the rat striatum. In situ hybridization histochemistry was used either in combination with retrograde labeling of striatonigral neurons to determine the projection site of A2a receptor expressing neurons, or on consecutive thin sections to address the putative coexpression of the A2a receptor with the D1 or D2 receptors in individual neurons. The A2a receptor is mainly expressed by neurons projecting to the globus pallidus and expressing also the dopamine D2 receptor and enkephalin, but very sparsely by neurons projecting to the substantia nigra that express the dopamine D1 receptor and substance P. We have further examined the regulatory effect of the A2 receptors on striatal gene expression using in situ hybridization histochemistry and quantitative autoradiography. Rats unilaterally depleted in dopamine by an unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway used as a model of Parkinson's disease subsequently received chronic injections of saline or the adenosine receptor antagonist caffeine. Intact rats were chronically treated with either saline, caffeine alone, caffeine with N-ethyl-carboxamidoadenosine (an equipotent A1 and A2 agonist), or caffeine with cyclohexyladenosine (a more selective A1 agonist).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. 768 65

In the present study, we have re-examined the heterogeneous nature of intrastriatal striatal transplants derived from embryonic day 14-15 rat striatal primordia implanted into the previously excitotoxically lesioned striatum of adult rats, using in situ hybridization histochemistry to localize neurotransmitter-related messenger RNAs. These grafts are characterized by discrete patches of DARPP-32 messenger RNA expression, which cover approximately one-third of the cross-sectional graft area. The messenger RNAs encoding for preproenkephalin (the enkephalin precursor), preprotachykinin (precursor to substance P), choline acetyltransferase, as well as the D1 and D2 dopamine receptors, which are abundant in the normal striatum, were all present in the striatal grafts and were expressed almost exclusively in the DARPP-32-positive graft regions. In these graft regions, the expression of the neurotransmitter-related messenger RNAs was generally similar to that seen in the intact striatum, although the level of expression of preproenkephalin and preprotachykinin messenger RNAs varied notably among the patches of expression. Cellular analysis performed on individual patches showed that the expression per cell of preproenkephalin and preprotachykinin messenger RNAs was inversely related, such that patches with higher than normal preproenkephalin messenger RNA levels displayed lower than normal preprotachykinin messenger RNA levels, and vice versa. Moreover, messenger RNA expression for the dopamine D2 receptor was overall lower than that for the dopamine D1 receptor, both with respect to the level per cell and the number of positive cells within the DARPP-32 patches. Glutamate decarboxylase messenger RNA was expressed throughout the grafts, in 98% of all neurons located in the DARPP-32-positive regions and in 75% of all neurons in the non-DARPP-32 regions of the graft. Interestingly, the cellular expression of glutamate decarboxylase messenger RNA was considerably higher in the non-DARPP-32 expressing regions than that in the DARPP-32 messenger RNA-rich areas, where it approximated that of the intact striatum. Furthermore, grafted neurons located outside the DARPP-32-expressing regions displayed similar levels of expression to those found in the overlying cortex and in the closely adjacent globus pallidus. To further characterize the DARPP and non-DARPP graft compartments, messenger RNAs encoding the alpha 1 and beta 2 subunits of the GABAA receptor were studied. These receptor subunits, which exhibit a high expression in the host cortex and pallidum but little in the intact striatum, were found in discrete patches situated outside, but often closely associated with, the DARPP-32-rich areas of the graft.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurotransmitter-related gene expression in intrastriatal striatal transplants--I. Phenotypical characterization of striatal and non-striatal graft regions. 770 3

The cellular expression of the mRNAs encoding the dopamine D1 receptor, dopamine D2 receptor and the neuropeptides enkephalin and substance P was determined in fresh frozen sections of human post-mortem caudate nucleus from control and schizophrenic brains using the technique of radioactive in situ hybridisation coupled with computer-assisted image analysis. Measurements of silver grain densities and mean cross-sectional somatic areas revealed no significant differences in the expression of any of these four gene transcripts. Further, cell count estimates revealed that each of these four mRNAs was expressed by approximately 20% of caudate cells (neurones and glia) in both control and schizophrenic tissue. These data demonstrate that the cellular expression of the dopamine D1 and D2 receptors and the neuropeptides enkephalin and substance P mRNAs are stable post mortem and that the relative cellular abundance of these mRNAs is not altered in the caudate nucleus of schizophrenic brains when compared to controls. These findings draw into focus the possible sites of action of clinically prescribed neuroleptics and suggest that chronic neuroleptic treatment of patients displaying negative schizophrenic symptoms may 're-set' an underlying neurochemical imbalance within the caudate nucleus.
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PMID:Dopamine D1 receptor, D2 receptor, proenkephalin A and substance P gene expression in the caudate nucleus of control and schizophrenic tissue: a quantitative cellular in situ hybridisation study. 875 Aug 94

The role of 5-hydroxytryptamine (5-HT) receptor subtypes in acetylcholine (ACh) release induced by dopamine or neurokinin receptor stimulation was studied in rat striatal slices. The dopamine D1 receptor agonist SKF 38393 potentiated in a tetrodotoxin-sensitive manner the K(+)-evoked [3H]ACh release while SCH 23390, a dopamine D1 receptor antagonist, had no effect. [3H]ACh release was decreased by the dopamine D2 receptor agonist LY 171555 (quinpirole) and slightly potentiated by the dopamine D2 receptor antagonist haloperidol. The selective neurokinin NK1 receptor agonist [Sar9, met(O2)11]SP also potentiated K(+)-evoked release of [3H]ACh. GR 82334, a NK1 receptor antagonist, blocked not only the effect of [Sar9, met(O2)11]SP but also the release of ACh induced by the D1 receptor agonist SKF 38393. Among the 5-HT agents studied, only the 5-HT2A receptor antagonists ketanserin and ritanserin were able to reduce the ACh release induced by dopamine D1 receptor stimulation. Mesulergine, a more selective 5-HT2C antagonist, showed an intrinsic releasing effect but did not affect K(+)-evoked ACh release induced by SKF 38393. Methysergide and methiothepin, mixed 5-HT1/2 antagonists, as well as ondansetron, a 5-HT3 receptor antagonist, showed an intrinsic effect on ACh release, their effects being additive to that of SKF 38393. 5-HT2 receptor agonists were ineffective. However, the 5-HT2 agonist DOI was able to prevent the antagonism by ketanserin of the increased [3H]ACh efflux elicited by SKF 38393, suggesting a permissive role of 5-HT2A receptors. None of the above indicated 5-HT agents was able to reduce the ACh release induced by the selective NK1 agonist. The results suggest that 5-HT2 receptors, probably of the 5-HT2A subtype, modulate the release of ACh observed in slices from the rat striatum after stimulation of dopamine D1 receptors. It seems that this serotonergic control is exerted on the interposed collaterals of substance P-containing neurons which promote ACh efflux through activation of NK1 receptors located on cholinergic interneurons.
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PMID:5-HT2 receptor regulation of acetylcholine release induced by dopaminergic stimulation in rat striatal slices. 920 Apr 94

The cellular distribution of adenosine A2A receptor messenger RNA in the central nervous system was investigated using in situ hybridization with ribonucleotide probes. A specific expression was found in the dorsal (i.e. caudate putamen) and ventral (i.e. nucleus accumbens and olfactory tubercle) striatum, the lateral septum and in some cerebellar Purkinje cells. Simultaneous detection of radioactive and non-radioactive probes showed that the majority of adenosine A2A receptor messenger RNA-containing neurons in the dorsal and ventral striatum co-expressed dopamine D2 receptor messenger RNA and preproenkephalin A messenger RNA. However, a minor sub-population of neurons expressing adenosine A2A receptor messenger RNA, but not preproenkephalin A messenger RNA, was found in clusters along the ventral border of the nucleus accumbens. Only a small number of striatal neurons expressing dopamine D1 receptor or substance P messenger RNAs also expressed adenosine A2A receptor messenger RNA. Finally, in the ventral part of nucleus accumbens and in the olfactory tubercle a major sub-population of neurons expressed preproenkephalin A messenger RNA, but not adenosine A2A receptor messenger RNA. Cholinergic interneurons did not express adenosine A2A receptor messenger RNA. Thus, the extensive co-localization of adenosine A2A and dopamine D2 receptors previously described in the dorsal striatum extends into its ventral part. There is also a high degree of co-expression of adenosine A2A receptor messenger RNA and preproenkephalin A messenger RNA in the ventral striatum, but within this region several topologically defined sub-populations of neurons express only one of these transcripts. A majority of the adenosine A2A receptor messenger RNA-containing neurons in the lateral septum did contain preproenkephalin A messenger RNA, whereas only a few co-expressed dopamine D2 receptor messenger RNA. This detailed investigation demonstrates that most of the subcortical areas innervated by dopamine have an abundant, although restricted expression of the adenosine A2A receptor gene and that this receptor is expressed in very few cells outside these areas. These results predict that adenosine A2A receptors are involved not only in motor behaviour, but also in goal-oriented behaviours.
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PMID:Cellular expression of adenosine A2A receptor messenger RNA in the rat central nervous system with special reference to dopamine innervated areas. 928 69

The aim of the present study was to further characterize the involvement of the mesolimbic dopamine system in central blood pressure regulation, with particular emphasis on the interaction of this system with the effects of circulating vasopressin. In conscious rats we stimulated the release of endogenous dopamine from mesolimbic/mesocortical terminals by administration of the substance P analogue DiMe-C7 ([pGlu5, MePhe8, Sar9]-Substance P5-11; 10 nmol) into the ventral tegmental area. Chemical stimulation of the ventral tegmental area resulted in a significant increase in blood pressure and heart rate. These effects were prevented by either bilateral electrolytic lesions of the hypothalamic supraoptic nucleus or by systemic pretreatment with the dopamine D2 receptor antagonist raclopride (0.5 mg/kg). Stimulation of the ventral tegmental area also produced a marked increase in the expression of the proto-oncogene c-fos in the supraoptic nucleus and a significant increase in plasma vasopressin levels, suggesting activation of vasopressinergic neurons in this nucleus. However, this effect of stimulation of the ventral tegmental area was not significantly inhibited by pretreatment with raclopride. We suggest that the effects on blood pressure and heart rate of stimulation of the ventral midbrain by micro-injection of DiMe-C7 are the result of combined activation of both dopaminergic and non-dopaminergic cell bodies in this region. Stimulation of non-dopaminergic cells in the ventral midbrain may induce a moderate increase in plasma vasopressin levels by activation of the supraoptic nucleus. An additional stimulation of dopaminergic cells in the ventral midbrain allows the increase in circulating vasopressin levels to become manifest as a pressor response, possibly by inhibition of vasopressin-induced facilitation of baroreflex responses.
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PMID:A functional interaction between the mesolimbic dopamine system and vasopressin release in the regulation of blood pressure in conscious rats. 930 Apr 2

We investigated whether the two output pathways of the striatum are differently affected by the novel atypical drug risperidone and the conventional typical antipsychotic drug haloperidol. To this end, changes in mRNA levels of preproenkephalin-A, preproenkephalin-B, and preprotachykinin were determined in the rat striatum following chronic drug treatment for 14 days, using quantitative in situ hybridization. Furthermore, we studied the contribution of the dopamine D2 and serotonin 5-HT2A antagonist components of risperidone in establishing its effects on neuropeptide mRNA levels in the striatum. The results showed that both risperidone and haloperidol had major effects on the preproenkephalin-A mRNA and thus on the indirect striatal output route, whereas they had minor effects on preproenkephalin-B and preprotachykinin mRNA, contained by the direct output route. When both drugs were administered in the same dose, preproenkephalin-A mRNA was much more elevated by haloperidol than by risperidone. However, when doses of risperidone and haloperidol were modified to attain comparable dopamine D2 receptor occupancy, the drugs had comparable effects on preproenkephalin-A mRNA levels. It was further found that 5-HT2A/C receptor blockade with ritanserin had only modest effects on preproenkephalin-B and preprotachykinin mRNA levels and did not affect preproenkephalin-A mRNA levels. We conclude that risperidone and haloperidol, administered in the same dose, differently affect the striatal output routes. Furthermore, the results suggest that the effects of risperidone on neuropeptide mRNA levels are fully accounted for by its D2 antagonism and that no indication exists for a role of 5-HT2A receptor blockade in this action.
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PMID:Effects of risperidone and haloperidol on tachykinin and opioid precursor peptide mRNA levels in the caudate-putamen and nucleus accumbens of the rat. 951 39


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