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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

According to the dopamine hypothesis of schizophrenia, D2 receptor blockade is essential for a drug to have antipsychotic potency, and antipsychotic potency and D2 blockade are linearly related in vitro. To test this assumption in vivo, we have compared clinical response with central D2 dopamine receptor availability measured by 123I-iodobenzamide single photon emission tomography in two groups of schizophrenic patients. 6 patients were on typical antipsychotic drugs and 10 were on the atypical antipsychotic clozapine, including 2 patients from the first group. The patients on typical antipsychotics showed poor therapeutic response despite D2 receptor blockade. Significant clinical improvement occurred in all patients on clozapine, but at a lower level of D2 blockade by the drug. These findings suggest a more complex relation between D2 blockade and clinical efficacy than was previously thought.
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PMID:Clozapine, single photon emission tomography, and the D2 dopamine receptor blockade hypothesis of schizophrenia. 135 35

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

PET scan studies of regional brain energy metabolism in schizophrenia have hitherto not been consistent in demonstrating any specific perturbation in heterogenous groups of patients. In some studies there was a tendency to reduced metabolic values in several regions in chronic patients. The variance of metabolic rates also tended to be greater in the group of schizophrenic subjects, but rates for most patients overlapped with those of the controls. Studies of regional brain energy metabolism also failed to disclose consistent effects of clinical antipsychotic drug treatment in schizophrenic patients. PET measurements of dopamine receptor functions in the major basal ganglia using different radioligands for D2 dopamine receptors also gave inconsistent results. One group reporting elevated densities of D2 dopamine receptors in the major basal ganglia of drug-naive schizophrenic patients could not be confirmed. PET measurements of dopamine receptor binding demonstrated profound and selective effects of clinical antipsychotic drug treatment on D2 and D1 dopamine receptor occupancy in schizophrenic patients. All chemically different categories of antipsychotic drugs induced a substantial occupancy of D2 dopamine receptors in relation to clinical treatment. This effect has been shown to be dose dependent and fully reversible. It appears much earlier than the antipsychotic effect and it is also present in neuroleptic-resistant patients. Accordingly, neuroleptic resistance is not related to individual pharmacodynamic or pharmacokinetic factors. Drug resistance is in all probability related to heterogeneity of biologic factors causing schizophrenia. Some, but not all, of the antipsychotic drugs also induce a significant D1 dopamine receptor occupancy. This effect was most marked for the unconventional drug clozapine, which showed about the same degree of D1 and D2 dopamine receptor blockade when given in conventional clinical doses. Further refinements of the resolution of PET scan instruments in the years to come and the development and application of new tracers will supply powerful tools for the further search for fundamental alterations of brain function in schizophrenia.
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PMID:The current status of PET scanning with respect to schizophrenia. 138 21

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

The development of PET and in vivo ligand-binding techniques over the past decade has allowed the analysis of dopamine receptor functions in the basal ganglia of human subjects. Using ligands selective for the different subtypes of dopamine receptors, their gross distribution, total number of binding sites and affinity have been determined in the caudate-putamen of the living human brain. Recent studies in young, drug-naive schizophrenic patients failed to demonstrate a consistent alteration in the densities or affinities of D2 dopamine receptors in the basal ganglia of these subjects, contradicting the view that elevated densities of D2 dopamine receptors are a major pathophysiological mechanism in this disorder. PET measurements of D2 dopamine receptor occupancy in relation to clinical antipsychotic drug treatment demonstrated that all chemically different categories of antipsychotic drugs induced a marked occupancy of D2 dopamine receptors. This effect was dose-dependent and fully reversible. It appeared earlier than the antipsychotic effect and was also present in neuroleptic-resistant patients. Resistance to neuroleptic drugs is in all probability related to heterogeneity of biological factors causing schizophrenia. Some, but not all, antipsychotic drugs also induced a significant D1 dopamine receptor occupancy. This effect was most marked for the unconventional drug clozapine, which showed about the same degree of D1 as D2 dopamine receptor blockade when given in clinical doses.
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PMID:PET imaging of dopamine receptors in human basal ganglia: relevance to mental illness. 169 8

Competition by endogenous dopamine with the binding of D2 dopamine receptor ligands may be important in the interpretation of positron emission tomography (PET) neuroreceptor studies. PET studies with N-methylspiperone (NMSP) have revealed increased D2 dopamine receptors in schizophrenia, whereas studies with raclopride (RAC) have not detected such differences. This may be due, at least in part, to differences in competition with endogenous dopamine for ligand binding. To determine effects of endogenous dopamine on in vivo receptor binding, adult male rats were preinjected with amphetamine and reserpine prior to [3H]NMSP or [3H]RAC. Striatal to cerebellar ratios of ligand binding were determined. To approximate the conditions of a PET study, a kinetic model was employed to examine effects of pharmacologically increasing brain dopamine levels (amphetamine pretreatment) on PET ligand binding. In these experiments, tail veins and arteries were cannulated and kinetic parameters determined from normalized integral plots in rats treated with amphetamine prior to radioligand injection. Both [3H]NMSP (43.5%) and [3H]RAC (41.5%) binding were significantly decreased after amphetamine pretreatment, whereas after reserpine pretreatment [3H]RAC binding was increased (52.7%). Kinetic studies revealed a marked resistance of [3H]NMSP to competition with endogenous dopamine released by amphetamine. In contrast, kinetic parameters of [3H]RAC were markedly reduced at all time intervals. This suggests significant differences in competition with endogenous dopamine by [3H]NMSP and [3H]RAC, determined kinetically. These findings may have important implications for the interpretation of PET neuroreceptor studies.
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PMID:Effects of endogenous dopamine on kinetics of [3H]N-methylspiperone and [3H]raclopride binding in the rat brain. 177 31

Several groups have reported increased densities of D2 dopamine receptors in the basal ganglia of schizophrenic brains postmortem. The significance of this finding has been questioned, since an upregulation of receptor number may be a neuronal response to neuroleptic drug treatment. We have used positron emission tomography and [11C]raclopride to examine central D2 dopamine receptor binding in 20 healthy subjects and 18 newly admitted, young, neuroleptic-naive patients with schizophrenia. An in vivo saturation procedure was applied for quantitative determination of D2 dopamine receptor density (Bmax) and affinity (Kd). When the two groups were compared, no significant difference in Bmax or Kd values was found in the putamen or the caudate nucleus. The hypothesis of generally elevated central D2 dopamine receptor densities in schizophrenia was thus not supported by the present findings. In the patients but not in the healthy controls, significantly higher densities were found in the left than in the right putamen but not in the caudate nucleus.
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PMID:D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride. 196 28

The dopamine hypothesis is one of the major etiological hypotheses of schizophrenia. The well-established role of genetic factors in schizophrenia together with reports of increased D2 dopamine receptor densities in untreated schizophrenic patients support the D2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D2 dopamine receptor gene made it possible to test the involvement of the D2 dopamine receptor locus (DRD2) in a large Swedish and a smaller Californian schizophrenia pedigree. Using multipoint linkage analysis between schizophrenia and a genetic map that includes the DRD2 locus and assuming a dominant mode of inheritance, we were able to exclude the DRD2 locus with a lod score of -4.14 for the penetrance of 0.72 and with a lod score of -3.05 for the lower bound penetrance of 0.56. The area of exclusion (lod score, less than -2.00) extended 27 centimorgans. These results provide strong evidence against linkage of the D2 dopamine receptor gene region to schizophrenia in the two pedigrees investigated. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to aberrations in the DRD2 locus or the porphobilinogen deaminase locus. Our results do not support the D2 dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D2 dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D2 dopamine receptor subtypes by alternative RNA splicing.
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PMID:No linkage between D2 dopamine receptor gene region and schizophrenia. 206 95

Overexpression of the D2 dopamine receptor has been proposed to be part of the pathology of schizophrenia. The isolation of a D2 dopamine receptor clone has assisted the molecular characterization of D2 receptor. We have now isolated an identical rat clone along with two other clones--a second related rat clone (RD-2in) and a homologous bovine clone (BD-2in), both of which contain an insert encoding an additional 29 amino acids relative to the original rat clone (RD-2o). All three clones encode D2 receptor binding sites when expressed in COS-7 cells. The amino-acid insert encoded by D-2in lies in the domain of the receptor believed to interact with the GTP-binding proteins (G proteins) of various signal transduction pathways. By using oligonucleotide probes specific for either D-2o or D-2in RNA transcripts, we have found that the level of expression of the D-2in-encoded form of the receptor is seven times that of the D-2o form in the caudate nucleus, the richest brain source of D2 receptors.
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PMID:A second molecular form of D2 dopamine receptor in rat and bovine caudate nucleus. 213 98


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