Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interest in the role of monoaminergic mechanisms in schizophrenia has stimulated the development of specific radioligands that allow PET analysis of quantitative aspects of monoamine receptor subtypes in the living human brain. Clinical studies with such ligands have not consistently demonstrated specific alterations of the total populations of D1 and D2 dopamine receptors in the caudate putamen complex of drug-naive schizophrenic patients. However, recent studies using [11C]SCH 23390, a specific D1 dopamine receptor ligand, disclosed a highly significant reduction of ligand binding in pixel elements of the basal ganglia that normally contain high activity. This finding may be related to reduced D1 dopamine regulated transmission in subsets of neuronal pathways within the basal ganglia. D3, D4, and D5 receptor subtypes constitute minor fractions of the total number of dopamine receptors in the human brain. However, efforts to find selective ligands for D3 and D4 subtypes also show promise. Radioligands for monoamine receptors have also been used to follow drug effects on receptor subtypes in schizophrenic patients treated with different types of antipsychotic drugs. Such studies have allowed the analysis of relationships between occupancy of dopamine receptor subtypes and some clinical manifestations of drug treatment. Such studies with the selective D2 antagonist raclopride indicated quantitative relationships between the degree of D2 dopamine receptor occupancy in the basal ganglia and the extrapyramidal manifestations, as well as the antipsychotic action. Some of the currently available antipsychotic drugs also induced significant occupancy of D1 dopamine receptors. However, the selective D1 antagonist SCH 39166 in doses inducing a more than 70% occupancy of D1 dopamine receptors in the caudate putamen failed to induce an antipsychotic action. This indicates that, in contrast to D2 blockade, selective antagonism of D1-regulated pathways does not mediate antipsychotic action in schizophrenia. Some but not all antipsychotic drugs also induced high occupancy of neocortical 5HT2A receptors. Because selective 5HT2A antagonism does not appear to be an efficient treatment for schizophrenia, it seems most likely that 5HT2A receptors and, perhaps, D1 receptors act in concert to modify aspects of the mandatory D2 blockade to induce antipsychotic actions. Computer graphic methods for image analysis add new dimensions to brain imaging research, allowing three-dimensional visualization of receptor populations computed from molecular PET data. This will make possible further exploration of the detailed molecular compartmentalization of the human brain using radioligand binding.
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PMID:Utilization of radioligands in schizophrenia research. 758 17

The correlation between the clinical activity of antipsychotic agents and their affinity for the D2 dopamine receptor has been the mainstay of the hypothesis that schizophrenia is due to excessive dopaminergic function. More recently, the unique clinical profile of the atypical antipsychotic clozapine has been proposed to involve actions on additional receptor systems. In particular, the high affinity of clozapine for the 5HT2A receptor subtype has been suggested to contribute to its reduced side-effect liability, greater efficacy and its activity in therapy-resistant schizophrenia. We have used the highly selective 5-HT2A antagonist MDL 100,907 to explore the contribution of 5-HT2A receptor blockade to antipsychotic activity. Biochemical, electrophysiological and behavioral studies reveal that selective 5HT2A receptor antagonists have the preclinical profile of an atypical antipsychotic. The limited clinical evidence available also suggests that compounds producing 5-HT2A receptor blockade are effective, in particular, against the negative symptoms of schizophrenia.
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PMID:The role of 5-HT2A receptors in antipsychotic activity. 779 9

The dopaminergic system implicated in human disorders such as Parkinson's disease, schizophrenia and prolactinomas, exerts its effects through several dopamine receptors. The diversity of the dopaminergic system has been revealed by the application of molecular biology techniques to this system, which allowed the identification of five different types of dopamine receptors to date. Even though the structure of these receptors has now been identified, their physiological roles are still under investigation. The coupling of the D1 and D2 dopamine receptor to second messengers has been investigated using cell lines transfected with the cDNAs of these receptors. However, until recently, there was no technique allowing non-invasive real-time measurement of the metabolic activity of cells after agonist stimulation. We present here real-time measurement of events induced by dopaminergic agents on either the D1 or the D2 dopamine receptors using a novel technique employing a silicon-based microphysiometer.
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PMID:Dopaminergic activity measured in D1- and D2-transfected fibroblasts by silicon-microphysiometry. 845 May 4

Genes that regulate dopamine (DA) receptors may underlie the overactive DA system in schizophrenia. Since it is known that there is an abnormally reduced or absent regulation of the DA D2 receptor by the DA D1 receptor in the postmortem schizophrenia brain, the human DA D1 receptor gene was sequenced from genomic deoxyribonucleic acid (DNA) of seven schizophrenic individuals. The tissues from two schizophrenics had previously been found to have a reduced link between DA D1 and D2 receptors. The D1 receptor genes were amplified by the polymerase chain reaction, subcloned, and sequenced. Although three DNA polymorphisms were found, the deduced amino acid sequence of the DA D1 receptor was normal in these tissues.
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PMID:Schizophrenia: dopamine D1 receptor sequence is normal, but has DNA polymorphisms. 847 Nov 24

Because dopamine (DA) D2 receptors are a target in neuroleptic therapy and have been found to be elevated in schizophrenia, the human DA D2 receptor gene was examined for possible abnormalities in schizophrenia. Moreover, since D2 receptors in psychosis have a reduced coupling to D1 receptors, the cytoplasmic third loop of D2 was chosen for deoxyribonucleic acid (DNA) sequencing, since this region is essential for coupling to G-proteins. This region also contains exon 5, which is expressed in the long form of D2, but not in the short form of D2. In eight schizophrenia cases, this region had normal exon sequences (exons 4, 5 and 6), and normal sequences at its intron-exon junctions. However, exon 6 contained three DNA polymorphic base changes, and introns 4 and 5 revealed three missing bases and two polymorphic base changes, none of which would be expected to alter the D2 receptor protein in schizophrenia.
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PMID:Schizophrenia: normal sequence in the dopamine D2 receptor region that couples to G-proteins. DNA polymorphisms in D2. 847 Nov 25

Our purpose was to test the dopamine D2 receptor gene (DRD2), the tyrosine hydroxylase (TH) gene and the monoamino oxydase A (MAO-A) gene for linkage to schizophrenia and bipolar disorders. We have analyzed seven Italian families with schizophrenia and four families with bipolar disorders for a total of 68 individuals; 32 individuals were affected. Diagnoses were made using the structured clinical interview Schedule for Affective Disorders and Schizophrenia, Lifetime version (SADS-L). The results of our study provide no evidence of linkage between alleles at D2 dopamine receptor loci and schizophrenia or bipolar disorders. The markers TH gene and MAO-A gene give slightly positive or negative results suggesting the utility of further analysis on more informative families.
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PMID:No evidence of linkage between schizophrenia and D2 dopamine receptor gene locus in Italian pedigrees. 871 Jan 85

Sensorimotor gating of the startle reflex is impaired in humans with schizophrenia and in rats after mesolimbic D2 dopamine receptor activation. The loss of startle gating after D2 activation in rats has been used as an animal model of impaired sensorimotor gating in schizophrenia, because the ability of antipsychotics to restore startle gating in D2-activated rats correlates significantly with antipsychotic clinical potency. Substantial evidence indicates that the pathophysiology of schizophrenia includes structural and functional deficits in prefrontal and temporal regions, particularly the dorsolateral prefrontal cortex and the hippocampus and parahippocampal gyrus. The present study assessed startle gating in adult rats after ibotenic acid lesions of the medial prefrontal cortex or ventral hippocampus. Medial prefrontal cortex lesioned rats exhibited normal startle amplitude and normal sensorimotor gating, as reflected by prepulse inhibition (PPI) of the startle reflex. Hippocampus lesioned rats exhibited elevated startle amplitude, and similar to rats with medial prefrontal cortex lesions, did not show significant changes in basal PPI. Low doses of the mixed dopamine agonist apomorphine did not significantly reduce PPI in sham lesioned rats, but significantly disrupted PPI in both medial prefrontal cortex- and ventral hippo-campus lesioned rats. These data are consistent with the hypothesis that cell damage in frontal and temporal cortex increases the sensitivity to the sensorimotor gating-disruptive effects of dopamine receptor activation.
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PMID:Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats. 871 Oct 61

Among the brain imaging techniques developed during the past two decades positron emission tomography has the highest sensitivity, allowing the analysis of specific neurotransmitter mechanisms in the living human brain. By using a combination of selective ligands labelled with positron emitting isotopes, D1 and D2 dopamine, serotonin 5HT2 and benzodiazepine receptors were examined in schizophrenic patients (DSM-IIIR) and healthy control subjects. With this technique receptor populations could be excellently visualized and quantified with regard to number and binding characteristics in several brain regions. The characteristics of total D1 and D2 dopamine receptor populations in the caudate and putamen did not differ significantly in young drug naive schizophrenic patients and age matched control subjects. On the other hand, there was a highly significant reduction of the D1 signal in high intensity regions of the basal ganglia when [11C]SCH 23390, a selective D1 dopamine receptor antagonist, was used. These results suggest the possibility of a reduced D1 dopamine receptor density in the patch compartment of the basal ganglia in schizophrenia. For 5HT2 and benzodiazepine receptors no major alteration of receptor characteristics was observed in several neocortical and limbic brain regions.
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PMID:PET imaging of neuroreceptors in schizophrenia. 877 55

Central D2 dopamine receptor occupancy may be a useful measure to establish clinical guidelines for optimal antipsychotic drug treatment. The use of positron emission tomography (PET) to explore quantitative relationships among D2 receptor occupancy and clinical effects depends on the reliability of such measurements. The calculation of D2 receptor occupancy using [11C]raclopride is routinely based on a ratio-equilibrium analysis, in which the ratio of radioactivity concentration in the striatum to that in the cerebellum is determined. To examine the reliability of such ratios, a test-retest analysis was performed in four schizophrenic patients treated with haloperidol decanoate. PET experiments with [11C]raclopride were repeated in each subject during the same day. The putamen to cerebellum ratio (P/C ratio) ranged from 1.44 to 1.07 among the four patients, corresponding to a D2 receptor occupancy of 62 to 71%. In each subject, the P/C ratios remained highly similar, with quotients 0.98, 1.01, 1.04 and 1.06 between the two experiments. The high test-retest reproducibility of the P/C ratios indicates that measurements of D2 receptor occupancy with the present methods are highly reliable, and support the further use of PET to optimize the drug treatment of schizophrenia.
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PMID:Test-retest reliability of central [11C]raclopride binding at high D2 receptor occupancy. A PET study in haloperidol-treated patients. 891 56

The two most important afferent projections to the striatum contain glutamate and dopamine, respectively. Excitotoxic damage resulting from excessive stimulation of the N-methyl-D-aspartate subtype of glutamate receptor has been implicated in pathophysiology of ischaemic stroke, hypoglycaemic brain damage and Huntington's disease. We studied the ability of the dopamine system to modify the anatomical, neurochemical and behavioural consequences of glutamatergic toxicity in the striatum. In a first set of experiments, the specific N-methyl-D-aspartate receptor agonist quinolinate was injected unilaterally into the striatum of rats pretreated with one of (i) intraperitoneal (i.p.) saline (controls); (ii) i.p. haloperidol, a D2 dopamine receptor agonist; or (iii) 6-hydroxydopamine lesion of the ipsilateral nigrostriatal tract. Quinolinate-induced striatal damage, as assessed by morphometric and neurochemical criteria, was significantly attenuated in the animals with 6-hydroxydopamine lesions and in those pretreated with haloperidol, compared with saline-pretreated controls. There were no significant differences between the 6-OHDA and haloperidol groups. In a second set of experiments, animals received (i) bilateral intrastriatal quinolinate plus perioperative i.p. saline; (ii) bilateral intrastriatal quinolinate plus i.p. haloperidol; or (iii) bilateral intrastriatal saline. Again, the quinolinate-lesioned animals treated with perioperative haloperidol had significantly less striatal damage than the bilateral quinolinate rats. Behavioural assessment in the Morris Water Maze showed the bilateral quinolinate+haloperidol group to be significantly less impaired on a spatial acquisition task than the bilateral quinolinate animals. Measures of spontaneous daytime motor activity showed significant differences in average speed and rest time between the bilateral quinolinate+haloperidol rats and the bilateral quinolinate group. The performance of the bilateral quinolinate+haloperidol group was not significantly different from that of controls on any of the behavioural tasks. These results indicate an important role for D2 dopamine receptor-mediated mechanisms in striatal excitotoxicity. Since the excitotoxic process involves the same fundamental signalling mechanism that is involved in normal glutamatergic transmission, these findings imply an ability of D2 receptor blockade to modify glutamate signalling in the striatum. These results may have implications for treatment strategies in ischaemic stroke, hypoglycaemic brain damage and schizophrenia.
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PMID:Dopamine-glutamate interactions in the striatum: behaviourally relevant modification of excitotoxicity by dopamine receptor-mediated mechanisms. 893 42


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