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)

The postsynaptic effects of dopamine in the striatum are mediated mainly by receptors encoded by D1, D2, and D3 dopamine receptor genes. The D1 and D2 genes are the most widely expressed in the caudate-putamen, the accumbens nucleus, and the olfactory tubercle. Several anatomical studies, including studies using in situ hybridization with oligonucleotide and cDNA probes, have suggested that D1 and D2 receptors are segregated into distinct efferent neuronal populations of the striatum: D1 in substance P striatonigral neurons and D2 in enkephalin striatopallidal neurons. In contrast, on the basis of several in vivo and in vitro studies, other authors have suggested the existence of an extensive colocalization of D1 and D2 in the same striatal neurons. Our study was undertaken in order to analyze in detail the expression of the D1 and D2 receptor genes in the efferent striatal populations, with special reference to the various striatal areas, and to yield insights into the question about D1 and D2 mRNA localization in the striatum. We have, therefore, used highly sensitive digoxigenin- and 35S-labeled cRNA probes to address this question. The present results demonstrate that the D1 and D2 receptor mRNAs are segregated, respectively, in substance P and enkephalin neurons in the caudate-putamen and accumbens nucleus (shell and core) and in the olfactory tubercle (for their largest part). A very small percentage of neurons may coexpress both genes. These results confirm that the D1 and D2 receptor genes are expressed in distinct populations of striatal efferent neurons in the normal adult rat.
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PMID:D1 and D2 dopamine receptor gene expression in the rat striatum: sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAs in distinct neuronal populations of the dorsal and ventral striatum. 763 23

The D3 dopamine receptor, belonging to the D2-like receptor subfamily, displays both specific pharmacology and a unique pattern of expression, especially compared to the D1 and D2 receptors. A rat D3 complementary RNA probe labelled with [35S]UTP was used to map the neurons expressing the D3 receptor gene in the rat brain. In particular, we identified the phenotype of the neurons containing D3 messenger. RNA in the nucleus accumbens, with respect to the striatal segregated populations of enkephalin and substance P neurons, by using strategies of double in situ hybridization. In addition, comparison with D1 and D2 receptor gene expression was performed to study the potential co-localization of several dopamine receptors within the same neurons in the ventral striatum. The highest level of D3 messenger RNA was detected in the islands of Calleja and the nucleus accumbens. Other areas such as the caudate-putamen, some hypothalamic, thalamic and cortical areas and lobule 10 of the cerebellum also contained low but significant levels of D3 messenger RNA. Our results demonstrate that the D3 receptor is co-expressed either with D1 or with D2 receptor, both in the core and shell regions, in a subpopulation of substance P and enkephalin neurons, respectively. They also suggest that a significant part of the accumbal neurons only express either D1 or D2, without co-expression with the D3 receptor. These data imply that dopamine in the nucleus accumbens may act on each population of efferent neurons via the co-expression of two distinct dopamine receptors (D1+D3 or D2+D3), and that synergistic D1-like/D2-like effects may occur at the level of a single neuron, through the co-expression of D1 and D3 receptors in a significant proportion of substance P neurons (16% or 26% in the core and shell regions, respectively.
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PMID:Expression of the D3 dopamine receptor in peptidergic neurons of the nucleus accumbens: comparison with the D1 and D2 dopamine receptors. 878 37

The D3 dopamine receptor, a D2-like receptor, is selectively expressed in the ventral striatum, particularly in the shell of nucleus accumbens and islands of Calleja, where it is found in medium sized substance P neurons. The latter co-express the D1 receptor whose interaction with the D3 receptor was studied by treating rats with selective agonists and antagonists. In agreement with the opposite cAMP response, they mediate in cultured neuroblastoma cells, the D1 and D3 receptors exerted opposite influences on c-fos expression in islands of Calleja. However, in agreement with the synergistic influence of cAMP on D3 receptor-mediated mitogenesis on the same cultured cells, D1 and D3 receptor stimulation in vivo synergistically enhanced preprotachykinin mRNA in the shell of accumbens. This indicates that the two receptor subtypes may affect neurons in either synergy or opposition according to the cell or signal generated. Levodopa-induced behavioral sensitization in hemiparkinsonian rats is another example of D1/D3 receptor interaction. Hence repeated levodopa administration induces the ectopic appearance of the D3 receptor in substance P/dynorphin, striatonigral neurons of the dorsal striatum. This induction is secondary to D1 receptor stimulation in neurons of the denervated side and fully accounts for the sensitization, i.e. the increased behavioral responsiveness to levodopa. During brain development, a similar process could operate to control the late appearance of the D3 receptor in D1-receptor bearing neurons of the ventral striatum at a time at which they start to be innervated by dopamine neurons. Finally, taking into account a variety of genetic, developmental, neuroimaging and pharmacological data, we postulate that imbalances between the levels of D1 and D3 receptors in the same neurons could be responsible for schizophrenic disorders.
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PMID:Functional implications of multiple dopamine receptor subtypes: the D1/D3 receptor coexistence. 965 37

Using double in situ hybridization, we found extensive coexpression of dopamine D1 and D3 receptor (D1R and D3R) mRNAs in neurons of the island of Calleja major (ICjM) and ventromedial shell of nucleus accumbens (ShV), respectively. Thus, at least 79 and 63% of D3R mRNA-expressing neurons in ICjM and ShV also expressed the D1R mRNA. Coexpression of D1R and D3R mRNAs was found to occur in substance P (SP) mRNA-expressing neurons in both areas, suggesting SP mRNA as a marker of the activity of coexpressing neurons. Administration of SKF 38393, a D1R receptor agonist, increased c-fos mRNA in ICjM, whereas administration of quinpirole, a D2R/D3R agonist, decreased it; SCH 23390, a D1 R antagonist and nafadotride, a preferential D3R antagonist, given alone, had effects opposite to those of the corresponding agonists. These data indicate that basal c-fos expression in ICjM is maintained by endogenous dopamine acting tonically upon two receptor subtypes subserving opposite effects on the same cell. However, in ShV, whereas SKF 38393 also increased c-fos mRNA, quinpirole had no effect, a difference presumably reflecting the lower fraction of neurons coexpressing D1R and D3R in this area. In contrast, in ShV from reserpine-treated rats, SKF 38393 increased SP mRNA and quinpirole potentiated this effect. These contrasting interactions of D1R- and D3R-mediated signalling events, i.e. in either opposite or synergistic directions, most likely occurring at the single cell level, may serve to increase the dopamine response threshold of the target cells in ICjM and to maintain a strong tonic activity of ShV neurons.
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PMID:Coexpression of dopamine D1 and D3 receptors in islands of Calleja and shell of nucleus accumbens of the rat: opposite and synergistic functional interactions. 975 Nov 40

The D3 receptor is recognized with high affinity by all antipsychotics and selectively expressed in limbic brain areas participating in the central of emotions, motivation and reward. In transfected cultured cells, stimulation of the D3 receptor inhibits cAMP formation and increases mitogenesis, which, in turn, is potentiated by activation of the cAMP cascade. This suggests that both opposite and synergistic interactions occur between the D3 receptor and the cydic AMP pathway, possibly underlying D1/D3 receptor interactions. In fact, D1 and D3 receptors colocalize in the islands of Calleja, in which they interact in opposition on c-fos mRNA expression, and in the shell of nucleus accumbens, in which they interact in synergy on substance P mRNA expression. The expression of the D3 receptor is highly dependent of the dopamine innervation: lesion of ascending dopamine neurons reduces D3 receptor mRNA and binding in the shell of nudeus accumbens, by deprivation of an unknown factor of dopamine neurons, distinct form dopamine and its cotransmitters. In agreement, expression of the D3 receptor in neurons during rat brain development starts after the settlement of dopamine innervation during the first postnatal week. However, in adult rats with a unilateral lesion of dopamine neurons, repeated treatment with levodopa rescues D3 receptor expression in the shell of nudeus accumbens and induces this expression in the dorsal striatum, a region controlling movements in which the D3 receptor is normally absent. This induction seems responsible for the behavioral sensitisation, i.e. increased responsiveness to levodopa. These observations suggest a role of the D3 receptor in the progressive increase in the therapeutic efficacy of levodopa in the initial treatment of Parkinson's disease, and/or its adversive motor and psychopathological effects during long-term treatment. Finally, various pharmacological and genetic data suggest a role of the D3 receptor in drug addiction and schizophrenia, the treatment of which could benefit from selective D3R agents.
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PMID:[Function and therapeutic potential of the dopamine D3 receptor]. 1010 7

L-DOPA-induced dyskinesias are one of the main problems encountered in treating patients with Parkinson's disease (PD). They are induced by the antiparkinsonian medications and primarily related to the degree of dopaminergic depletion, as shown by the fact that they tend to appear several years after the onset of the disease. Do the initial therapeutic decisions taken in treating a PD patient influence the point at which dyskinesias first occur? This question is raised in view of the apparent priming phenomenon that occurs in first exposure to L-DOPA. L-DOPA administrated to an MPTP intoxicated monkey rapidly corrects the animals' motor symptoms but generate dyskinesias. In contrast, the administration of dopaminergic agonists with a long half-life has a similar therapeutic effect but without inducing dyskinesias. However, a parkinsonian monkey that had received L-DOPA and developed dyskinesias, which were subsequently abolished when the treatment was withdrawn for several months, proceeded to develop dyskinesias when treatment with dopaminergic agonists with long half-life was introduced. The monkeys' previous exposure to L-DOPA (i.e. priming) thus increased its susceptibility to develop dyskinesias after exposure to drugs which would not otherwise have had this effect. Pulsatile activation of type D2 dopamine receptors is reported to be the principal factor in the triggering of dyskinesias and may well be involved in the priming phenomenon. While the pathophysiological basis of priming is not yet known, the phenomenon would not appear to be related to a hyperexpression of dopamine receptors (types D1 and D2) in the sensorimotor striatum. The results of recent experiments have given rise to several different hypothesis for the mechanisms involved in priming: the role of internalization of dopamine receptors after administration of dopaminergic drugs; change in the distribution of D3 dopamine receptor; changes in the expression of peptides (substance P, enkephalin) in efferent neurons of the striatum; and reorganization of connections at the level of the dopaminergic neurons and their target tissue. While many questions remain unanswered, it may well be that the initial therapeutic decisions taken when treating de novo patient are crucial in trying to delay the onset of dyskinesias.
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PMID:[Development of dyskinesias induced by treatment for Parkinson's disease: potential role of first exposure to L-DOPA (or phenomenon of priming)]. 1074 93

While levodopa-induced neurochemical changes have been studied in animal models of Parkinson's disease, very little is known regarding the effects of levodopa administration in normal animals. The present study investigates the effects normal and MPTP-lesioned mice chronically treated with two different doses of levodopa. We assess changes in striatal dopamine (DA) receptor binding, striatal DA receptor mRNA levels and striatal neuropeptide precursor levels (preproenkephalin-A [PPE-A]; preprotachykinin [PPT]; preproenkephalin-B [PPE-B]). The extent of the lesion was measured by striatal DA transporter binding and stereological estimation of the number of tyrosine hydroxylase immunoreactive neurones in the substantia nigra pars compacta (SNc). In non-lesioned animals, chronic levodopa treatment induced an increase in PPE-A mRNA, whereas both D3R binding and PPE-B mRNA levels were dramatically increased in the lesioned animals in a dose dependent manner. The present results show that chronic levodopa administration may induce pathophysiological changes, even in the absence of a lesion of the nigro-striatal pathway, suggesting that the sensitization process involves predominantly the indirect striatofugal pathway in non-lesioned animals, whereas the direct pathway is primarily involved in lesioned animals.
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PMID:Pattern of levodopa-induced striatal changes is different in normal and MPTP-lesioned mice. 1261 25

Drugs abused by humans are thought to activate areas in the ventral striatum of the brain that engage the organism in important adaptive behaviors, such as eating. In support of this, we report here that striatal regions of sugar-dependent rats show alterations in dopamine and opioid mRNA levels similar to morphine-dependent rats. Specifically, after a chronic schedule of intermittent bingeing on a sucrose solution, mRNA levels for the D2 dopamine receptor, and the preproenkephalin and preprotachykinin genes were decreased in dopamine-receptive regions of the forebrain, while D3 dopamine receptor mRNA was increased. While morphine affects gene expression across the entire dopamine-receptive striatum, significant differences were detected in the effects of sugar on the nucleus accumbens and adjacent caudate-putamen. The effects of sugar on mRNA levels were of greater magnitude in the nucleus accumbens than in the caudate-putamen. These areas also showed clear differences in the interactions among the genes, especially between D3R and the other genes. This was revealed by a novel multivariate analysis method that identified cooperative interactions among genes, specifically in the nucleus accumbens but not the caudate-putamen. Finally, a role for these cooperative interactions in a load-sharing response to perturbations caused by sugar was supported by the finding of a different pattern of correlations between the genes in the two striatal regions. These findings support a major role for the nucleus accumbens in mediating the effects of naturally rewarding substances and extend an animal model for studying the common substrates of drug addiction and eating disorders.
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PMID:Opiate-like effects of sugar on gene expression in reward areas of the rat brain. 1513 21

Ropinirole, which is a non-ergot dopamine agonist derivative, exerts therapeutic benefits in Parkinson's disease (PD). Based on recent studies implicating dopamine receptors 2 and 3 (D2R and D3R) as possible targets of ropinirole, we over-expressed these dopamine receptor genes in the dopamine-denervated striatum of rodents to reveal whether their over-expression modulated ropinirole activity. Adult Sprague-Dawley rats initially received unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. At 1 month after surgery, successfully lesioned animals (3 or less forelimb akinesia score, and 8 or more apomorphine-induced rotations/min over 1 h) were randomly assigned to intrastriatal injection (ipsilateral to the lesion) of blank lentiviral vector, D2R, D3R or both genes. At about 5 months post-lesion, ropinirole (0.2 mg/kg, i.p.) was administered daily for 9 consecutive days. The subtherapeutic dose of ropinirole improved the use of previously akinetic forelimb and produced robust circling behavior in lesioned animals with striatal over-expression of both D2R and D3R compared to lesioned animals that received blank vector. In contrast, the subtherapeutic dose of ropinirole generated only modest motor effects in lesioned animals with sole over-expression of D2R or D3R. Western immunoblot and autoradiographic assays showed enhanced D2R and D3R protein levels coupled with normalized D2R and D3R binding in the ventral striatum of lesioned animals with lentiviral over-expression of both D2R and D3R relative to vehicle-treated lesioned animals. Immunohistochemical analyses showed that D2R and D3R GFP fluorescent cells colocalized with enkephalin and substance P immunoreactive medium spiny neurons. These data support the use of the subtherapeutic dose of ropinirole in a chronic model of PD.
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PMID:Overexpression of D2/D3 receptors increases efficacy of ropinirole in chronically 6-OHDA-lesioned Parkinsonian rats. 1757 46