Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The addition of a D2 agonist such as bromocriptine to L-Dopa therapy can often improve the response of patients with Parkinson's disease dramatically. Simultaneous activation of D1 and D2 dopamine receptors can produce a synergistic effect on locomotion in rats and primates. However, despite the importance of this addition of a D2 agonist to the D1/D2 agonist L-Dopa, little is known of the sites of action of these agents. Recent work suggests that, in addition to D1 and D2 dopamine receptor sites in the striatum (caudate-putamen), L-Dopa and D1 agonists have important effects at D1 dopamine receptors in the substantia nigra. Animal experiments suggest that D1 and D2 dopamine receptor agonists probably also affect different outflow pathways from the striatum. An understanding of these pathways and how dopamine agonists affect them gives insight into some of the clinical problems experienced in treating Parkinson's disease (the "on-off" phenomenon, for example). D1/D2 dopamine receptors also differentially affect gene expression and regulation in the striatum. An understanding of the anatomical and biochemical location of the actions of dopamine receptor agonists will be important in maximizing the beneficial effects and minimizing the side-effects of both presently-used drugs and new treatments.
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PMID:Synergistic interactions of D1- and D2-selective dopamine agonists in animal models for Parkinson's disease: sites of action and implications for the pathogenesis of dyskinesias. 134 63

In mice pretreated with reserpine and alpha-methyl-DL-p-tyrosine (alpha MPT) to deplete central catecholamines, the D2 dopamine receptor-selective agonist, bromocriptine, at a dose of 10 mg/kg produced no locomotor activity. The D1-selective agonist, CY 208-243, generated a dose-dependent locomotor response in this animal model for Parkinson's disease; low doses elicited little or no effect while higher doses resulted in a short burst of locomotor activity (2 h). The combination of CY 208-243 and bromocriptine had a dramatic synergistic effect on locomotion. Most importantly, this combination of D1 and D2 agonists converted a brief (2 h) effect on locomotion to one which persisted for up to 6 h. These results suggest that the combination of D1 and D2 dopamine receptor agonists can affect both the intensity and the persistence of a locomotor response.
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PMID:Synergistic and persistent interaction between the D2 agonist, bromocriptine, and the D1 selective agonist, CY 208-243. 136 Mar 21

D2 dopamine receptor may be related with the pathogenesis of Parkinson's disease and schizophrenia. Furthermore, the antipsychotic drugs have high affinity for D2 dopamine receptor. We carried out the cloning of the genomic DNA for human D2 dopamine receptor and clarified the structure of this gene. Our isolated gene spans about 15 kbp and consists of seven exons interrupted by six introns. However, putative first exon was not yet identified. Spot blot hybridization analysis of cell sorter fractionated human chromosomal DNA with D2 receptor genomic DNA revealed the localization of this gene in the chromosome 11 fraction. We analyzed human genomic DNA by Southern blot hybridization with D2 dopamine receptor genomic DNA as a probe, but so far we could not find RFLP. Northern blot analyses of brain RNA of several animals and rat brain RNA after various treatments were carried out. Developmental changes of D2 dopamine receptor mRNA were observed in the rat brains.
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PMID:Structure and expression of human and rat D2 dopamine receptor genes. 136 62

Since the discovery that L-DOPA could alleviate the symptoms of Parkinson's disease, it has been assumed that the striatum is the site of action of the dopamine formed from L-DOPA. However, for the past 15 years, evidence has accumulated to suggest that dopamine is also released by the dendrites of dopamine neurons in the substantia nigra and D1 dopamine receptors in this region of the brain appear to play an important role in the actions of L-DOPA. Activation of D1 receptors in the substantia nigra may, in part, explain some of the synergistic effects of D1 and D2 agonists in animal models for Parkinson's disease. These effects are discussed in light of recent studies suggesting that dopamine, acting on D1 and D2 dopamine receptor subtypes, activates distinct efferent pathways from the striatum. Clinical studies suggest that these findings may have important implications for the treatment of Parkinson's disease.
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PMID:Dopamine receptor interactions: some implications for the treatment of Parkinson's disease. 137 62

Two major pharmacological classes of dopamine receptors exist in the central nervous system. These receptors have been designated as D1 or D2 based upon their differing pharmacology and influence on the cyclic AMP second messenger system. Different genes for the D1 and D2 dopamine receptors have been isolated and are found to be expressed in high abundance. Within the neostriatum, however the cellular distribution of the dopamine receptors is equivocal. Dopamine receptors are the targets for drugs used to treat neurological dysfunctions such as Parkinson's disease and schizophrenia, and thus knowledge of their specific cellular location is important for devising future therapeutic manipulations. Using retrograde labeling methods combined with immunofluorescence of various receptor amino acid sequences, this study has examined the postsynaptic distribution of striatal D2 dopamine receptors. We have found that the D2 dopamine receptor can be visualized on a minimum of 60% of the neurons projecting from the neostriatum to the substantia nigra. However, some 65% of all D2 receptor positive cells are represented by other intrinsic neurons of this basal ganglia nucleus.
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PMID:D2 dopamine receptor localization on striatonigral neurons. 143 5

The gene encoding the D2 dopamine receptor (DRD2) is located on human chromosome 11q23 and has been circumstantially associated with a number of human disorders including Parkinson's disease, schizophrenia, and susceptibility to alcoholism. To determine the physical structure of the DRD2 gene, we utilized cosmid cloning, isolation of yeast artificial chromosomes (YACs), and pulsed-field gel electrophoresis to construct a long-range physical map of human chromosome 11q23 linking the genes for the DRD2 and neural cell adhesion molecule (NCAM). The D2 dopamine receptor gene extends over 270 kb and includes an intron of approximately 250 kb separating the putative first exon from the exons encoding the receptor protein. The resulting physical map spans more than 1.5 mb of chromosome band 11q23 and links the DRD2 gene with the gene encoding the NCAM located 150 kb 3' of the DRD2 gene and transcribed from the same DNA strand. We additionally located the sites of at least four hypomethylated HTF islands within the physical map, which potentially indicate the sites of additional genes. High-resolution fluorescent in situ suppression hybridization using cosmid and YAC clones localized this gene cluster between the ApoAI and STMY loci at the interface of bands 11q22.3 and 11q23.1.
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PMID:Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11q23. 147 42

We used 123I-iodobenzamide-single photon emission computed tomography (IBZM-SPECT) in a prospective study to investigate 38 patients with parkinsonism (Hoehn and Yahr stage I to III) not previously treated with dopamimetic drugs. Thirty-four patients only showed symptoms of Parkinson's disease, and four patients showed, in addition, subtle clinical signs of progressive supranuclear palsy or multisystem atrophy. IBZM is a dopamine D2 receptor antagonist detectable by SPECT. We compared IBZM-SPECT results with clinical response to subcutaneous injections of the D1/D2 dopamine receptor agonist apomorphine (38 patients) and long-term dopamimetic therapy (31 patients). IBZM-SPECT results predicted a positive or negative response to apomorphine in 30 of 34 patients (apomorphine response in four patients was equivocal) and response to dopamimetic therapy in 27 of 31 patients. Thus, imaging of dopamine D2 receptors using readily available IBZM-SPECT seems to distinguish between L-dopa-responsive (most likely Parkinson's disease of Lewy body type) and L-dopa-unresponsive parkinsonism in patients not previously treated with dopamimetic drugs.
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PMID:123I-iodobenzamide-SPECT predicts dopaminergic responsiveness in patients with de novo parkinsonism. 154 16

Dopaminergic denervation supersensitivity has been implicated in the pathogenesis of levodopa-induced dyskinesias, the most common and limiting side effect in the drug treatment of Parkinson's disease, yet the mechanisms that mediate altered drug sensitivity remain poorly understood. In animals models, one key component of denervation supersensitivity is the enhanced efficacy of selective D1 agonists to stimulate locomotion. In rats with chronic dopamine depletion induced by 6-hydroxydopamine nigral lesion, the increased ability of D1 agonists to stimulate regional cerebral glucose utilization (RCGU) in the substantia nigra pars reticulata (SNr) has provided a metabolic correlate to the heightened motor response. In this study, we used the stimulation of RCGU in the SNr as a sensitive in vivo assay of D1 agonist effect to examine the time course of development of supersensitivity in rats following acute dopamine depletion with single doses of reserpine (5.0 mg/kg, i.p.) and alpha-methyl-p-tyrosine (AMPT; 100 mg/kg, i.p.). The stimulatory effect of the D1 agonist SKF 38393 (30 mg/kg) on RCGU in the SNr was first enhanced 6 hr after reserpine/AMPT injection and was maximally enhanced at 12-24 hr (relative 2-deoxyglucose uptake increased 32-51%; P less than 0.05). The response to SKF 38393 returned to control values 5 d after reserpine/AMPT injection. The single reserpine/AMPT injections depleted striatal dopamine to 1-2% of control values from 3-48 hr postinjection, whereas D1 and D2 dopamine receptor densities were unchanged at 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Rapid development of dopaminergic supersensitivity in reserpine-treated rats demonstrated with 14C-2-deoxyglucose autoradiography. 161 60

Recent evidence of functional interactions between D1 and D2 dopamine receptor subtypes has led to the concept that many of the behavioural effects of dopamine agonists occur only with activation of both receptor subtypes. Thus, combined treatment with dopamine agonists selective for each of the D1 and D2 receptors may be an effective therapy for Parkinson's disease, chiefly characterized by loss of central dopamine-containing neurons. In addition, recent hypotheses of the possible pathogenesis of this disorder have suggested that metabolism of dopamine by monoamine oxidase in the presynaptic terminal may contribute to the loss of dopaminergic cells, through the production of reactive by-products. Therefore, the effects of chronic (15 day) treatment of rats with different doses of (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a D2 receptor agonist), SKF 38393 (a D1 receptor partial agonist) or combinations of both drugs on levels of brain monoamines and some of their acidic metabolites were investigated. Little or no effects of the drugs were observed on measures of dopamine or noradrenaline when given separately, while each selective agonist dose-dependently reduced serotonin levels. Combined treatment with the two agonists produced profound effects on the catecholamines, but with no effect on 3,4-dihydroxyphenylacetic acid, the metabolite of dopamine produced by monoamine oxidase. In addition, the effects of combined treatment on serotonin levels were opposite of those of the drugs given independently. Concomitant treatment of animals with both D1 and D2 receptor agonists can therefore increase tissue levels of dopamine without increasing the potentially harmful metabolism of dopamine by monoamine oxidase.
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PMID:Chronic treatment with D1 and D2 dopamine receptor agonists: combined treatments interact to differentially affect brain levels of monoamines. 168 87

In the present study, quantitative in situ hybridization was used to analyse the effect of haloperidol treatment on D2 dopamine receptor gene expression in the rat caudate-putamen nucleus. Variations of D2 receptor mRNA level were studied and measured at the macroscopic level of densitometric analysis of X-ray film and at the microscopic level by counting of autoradiographic silver grains in striatal cells. Macroscopic analysis demonstrated that haloperidol treatment two times 1 mg/kg per day during seven, 14 and 21 days increased D2 receptor mRNA level in the caudate-putamen. Detailed microscopic analysis demonstrated a significant increase in D2 receptor mRNA in the two neuronal populations known to express the D2 receptor gene: medium-sized neurons previously identified as enkephalinergic neurons, and large-sized neurons previously identified as cholinergic neurons. The increase was more important in cholinergic neurons (+119%) than in enkephalinergic neurons (+54%). Haloperidol treatment did not modify the number of medium-sized enkephalinergic neurons expressing the D2 receptor mRNA. In contrast, it significantly increased the percentage of large-sized neurons containing D2 receptor mRNA (from 80 to 94%). These results demonstrate that haloperidol treatment acts at the gene level to modulate D2 receptor content in striatal dopaminoceptive neurons, and that the D2 receptor mRNA increase in postsynaptic neurons contributes to dopamine supersensitivity induced by neuroleptics in the rat. This suggests that dopamine acts trans-synaptically to control D2 receptor gene expression in target striatal neurons. These results suggest that modifications of D2 receptor gene expression may be part of the biological events that lead to the movement disorders induced by neuroleptic drugs or Parkinson's disease.
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PMID:Striatal neurons express increased level of dopamine D2 receptor mRNA in response to haloperidol treatment: a quantitative in situ hybridization study. 175 61


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