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)

The neuronal dopamine transporter/uptake site can be covalently labeled with the photoaffinity probe 1-(2-[bis-(4-fluorophenyl) methoxy]ethyl)-4-[2-(4-azido-3-[125I]iodophenyl)ethyl]piperazine [( 125I]FAPP) and visualized following sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography. Upon photolysis, [125I]FAPP specifically incorporated into a polypeptide of apparent Mr = 62,000 in membranes from both the putamen and the caudate nucleus of control, Alzheimer's, schizophrenia, and Huntington's diseased brain, and following complete deglycosylation, migrated as an Mr approximately 48,000 polypeptide. In parkinsonian postmortem putamen, however, there was no detectable photoincorporation of [125I]FAPP into the ligand binding subunit of the dopamine transporter. [125I]FAPP did specifically label the Mr 62,000 polypeptide of parkinsonian caudate, although with efficiencies of 20-50% of control. The asymmetrical loss of the dopamine transporter in Parkinson's diseased striatum was confirmed in reversible receptor binding experiments using [3H]GBR-12935 (3H-labeled 1-[2-(diphenylmethoxy) ethyl]-4-(3-phenylpropyl)piperazine). In parkinsonian putamen, mazindol competitively inhibited the binding of [3H]GBR-12935 with an estimated affinity (Ki approximately 2,000 nM) 10 times lower than in controls (Ki approximately 30 nM), while the affinity of maxindol for [3H]GBR-12935 binding in the caudate was equal to that seen with controls (Ki approximately 50 nM). The proportion of [3H]GBR-12935 binding sites recognized by mazindol with high affinity in Parkinson's diseased caudate was, however, reduced by 50-80%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The dopamine transporter is absent in parkinsonian putamen and reduced in the caudate nucleus. 198 18

All the patients (N = 94) of an outpatient clinic for schizophrenia were evaluated for the presence and severity of neuroleptic induced tardive dyskinesia. Fourty-four percent of the patients showed some degree of tardive dyskinesia. The proportion of patients with tardive dyskinesia increased directly with age and with number of years of neuroleptic treatment. Recent dose reduction exacerbated the syndrome. There were no gender differences in the clinic as a whole. Severity of dyskinesia correlated with anticholinergic drug use, with the piperazine/butyrophenone group of neuroleptics and with the use of depot-administered drugs. The depot correlation was highly significant in the under-30 age group.
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PMID:Tardive dyskinesia in schizophrenic outpatients: prevalence and significant variables. 610 15

Studies measuring reflective lateral eye movements (LEM) in schizophrenic patients revealed predominance of rightward LEMS, which was interpreted as suggesting left hemisphere overactivation in schizophrenia. In the present study LEM behaviour of medicated schizophrenics was compared to that of non-medicated patients. Rightward LEMs were predominant in a group of patients treated with phenothiazines with piperazine side chains, whereas among schizophrenics treated with non-piperazine drugs leftward LEMs were more predominant. This finding suggests that previous reports on LEM directionality in schizophrenia may have been confounded by neuroleptic medication. The possible effect of piperazine derivatives on hemispheric balance is discussed.
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PMID:Left hemisphere hyperactivity in schizophrenia: abnormality inherent to psychosis or neuroleptic side-effects? 612 5

Serotonin (5-hydroxytryptamine, 5-HT) receptors as well as dopamine receptors are important in connection with schizophrenia. In this study we evaluated the effects of the 5-HT1A receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) and 5-HT1B receptor agonist (1-(3-trifluoromethylphenyl)piperazine, TFMPP) on the single and paired rats' movement distance in an open-field. Generally animals are gregarious in their natural setting, so the presence of another companion might alter the effects of the drugs. Therefore we devised a video analysis system to pick up the two rats' movements individually through two CCD video cameras and objectively recorded two rats' movement for 30 minutes. Experimental rats were injected with 8-OH-DPAT (0.05, 0.25, 1.25, 6.25 mg/kg, s.c.) or TFMPP (0.12, 0.5, 2.0, 8.0 mg/kg, i.p.) and the control rats were injected with saline. In the single cases experiments, the rats were put alone into the open field after the injection. In the paired cases experiments, they were put into the open field with a companion rat after the injection. In the 8-OH-DPAT experiment, the movement distance of single cases showed dose dependent increase tendency and that of the 1.25 mg/kg group and the 6.25 mg/kg group showed significant increase, but that of paired cases did not show that tendency, on the contrary, the movement distance of 0.05 mg/kg group showed significant decrease. In the TFMPP experiment, the movement distance of 2.0 mg/kg groups showed significant increases in the single and the paired cases. These findings suggest that both 5-HT1A receptors and 5-HT1B receptors affect the rats' movement distance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effects of 5-HT1A receptor agonist and 5-HT1B receptor agonist on single and paired rats' behavior]. 754 36

1. Phencyclidine (PCP) reduces the latency of rats diving into a water-filled pool from a hidden platform, without stereotyped behavior. 2. The sigma-selective ligand, NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethyl-amine monohydrochloride), attenuates the effects of PCP in this procedure. 3. The serotonin2 (5-HT2) antagonist, ritanserin, and the sigma receptor ligands, 1-(cyclopropylmethyl)-4-[2'(4"-fluorophenyl)-2'-oxoethyl]- piperidine HBr (Dup734), 4-[2'-(4"-cyanophenyl)-2'-oxoethyl]-1- (cyclopropylmethyl)piperidine (XJ448), alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMY14802) and rimcazole similarly attenuate the effects of PCP. 4. The dopamine D2/sigma ligands, haloperidol and cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-2-methoxy-5-chloro-4- methylaminobenzamide (YM-09151-2) completely reverse the effects of PCP, whereas the same dose ranges of these drugs produce sedation. 5. The dopamine D2-selective antagonist, sulpiride, has no apparent effect on the PCP latency to the rat dive. 6. Thus, PCP-induced diving behavior was improved by sigma ligands and the 5-HT2 antagonist. This model of negative symptoms in an experimental animal will facilitate experiments on drug treatments for schizophrenia.
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PMID:The sigma-selective ligand NE-100 attenuates the effect of phencyclidine in a rat diving model. 771 58

The carrier molecule that transports dopamine (DA) across the synaptic membrane is known as the dopamine transporter (DAT). Depending on the ionic conditions, DAT may function as a mediator of both the inward directed DA transport known as the "reuptake" and the outward directed DA transport known as the "release." The functional significance of DAT is in the regulation of DA neurotransmission by terminating the action of DA in the synapse via reuptake. With use of DAT binding as a presynaptic marker to measure altered DA innervation, abnormalities of the DAT binding have been demonstrated in idiopathic Parkinson's disease, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity, and progressive supranuclear palsy. Moreover, the identification of DAT as the neuronal element that mediates the addictive properties of cocaine highlights its significance in cocaine addiction. Cocaine binding in the brain is heterogeneous, and there is an uneven distribution of the high- and low-affinity binding sites across the anatomical regions. Regional differences in ligand binding are observed by using both [3H]cocaine and the diphenyl-substituted piperazine derivatives known as the "GBR series" of ligands. The identification of compounds that inhibit the binding of medications for cocaine abuse. Furthermore, clarification of the various binding domains that may be relevant to transporter function in human neuropsychiatric disorders may lead to the development of new medications for schizophrenia, Tourette's disease, and drug addiction.
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PMID:Molecular, functional and biochemical characteristics of the dopamine transporter: regional differences and clinical relevance. 814 55

The effects of putative sigma receptor antagonists, BMY-14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine), rimcazole and SR-31742A (cis-3-(hexahydroazepin-1-yl)1-(3-chloro-4- cyclohexylphenyl)propene-1), on the development of behavioral sensitization induced by repeated administration of cocaine were investigated. Acute intraperitoneal injection of 15 mg/kg cocaine in rats induced moderate hyperactivity which mainly consisted of sniffing and rearing. These acute effects of cocaine were hardly affected by co-administration of the sigma receptor antagonists, except that BMY-14802 enhanced, but not significantly cocaine-induced locomotion. While repeated cocaine administration induced a progressive increase in stereotyped behaviors and resulted in sensitization, every sigma receptor antagonists tested attenuated the development of sensitization to cocaine. These prophylactic effects of sigma receptor antagonists against cocaine-induced sensitization were confirmed by the challenge test with cocaine alone after an abstinence. These results were consistent with results of our previous study which revealed that BMY-14802 blocked the sensitization to methamphetamine, another psychostimulant. Therefore, sigma receptors play a crucial role in the development of the psychostimulant-induced sensitization phenomenon, which is a pharmacological model of schizophrenia.
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PMID:sigma Receptor antagonists block the development of sensitization to cocaine. 883 47

Although there has been renewed interest in the serotonin (5-HT) system in schizophrenia, direct evidence for 5-HT dysfunction is limited. This study compares the responses of m-chlorophenyl-piperazine (mCPP), a 5-HT agonist, in first-episode schizophrenia and a known psychotogenic dopamine agonist, methylphenidate. Eighteen patients experiencing their first episode of psychosis and eight healthy controls received methylphenidate (0.5 mg/kg) and mCPP (0.1 mg/kg) intravenously. Behavioral assessments were done before and after the procedure, and a peak response to each agent was rated. Methylphenidate, but not mCPP, produced psychotic symptoms in patients. mCPP did decrease anxiety, hallucinations, and anger and increased agitation, somatic concern, and impaired understandability. Both agents had limited effects on controls. In conclusion, unlike methylphenidate, mCPP did not produce psychotic symptom activation in schizophrenic patients in, and its effects appeared to be nonspecific.
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PMID:The behavioral effect of m-chlorophenylpiperazine (mCPP) and methylphenidate in first-episode schizophrenia and normal controls. 898 89

3-([4-(4-Chlorophenyl)piperazin-1-yl]-methyl)-1H-pyrrolo-2, 3-beta-pyridine (L-745,870) is a dopamine D(4) selective antagonist that has been studied as a potential treatment for schizophrenia, with the expectation that it would not exhibit the extrapyramidal side effects often observed with the use of classical antipsychotic agents. The metabolism of L-745,870 in vivo was investigated in the rat, rhesus monkey, and human using liquid chromatography-tandem mass spectrometry and/or NMR techniques in conjunction with radiochemical detection. In all three species, two major metabolic pathways were identified, namely N-dealkylation at the substituted piperazine moiety and the formation of a novel mercapturic acid adduct. It is proposed that the latter biotransformation process involves the formation of an electrophilic imine methide intermediate, analogous to that produced from 3-methyl indole. This report appears to represent the first example of metabolic activation of a 3-alkyl-7-azaindole nucleus.
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PMID:Metabolism of A dopamine D(4)-selective antagonist in rat, monkey, and humans: formation of A novel mercapturic acid adduct. 1082 Jan 34

MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]++ +methy l-2-pyrrolidinone L-tartrate) is a novel selective sigma receptor ligand, currently being developed for the treatment of schizophrenia. MS-377 showed anti-phencyclidine (PCP), anti-dopaminergic and anti-serotonergic activities, and we anticipated that the anti-psychotic activities of MS-377 were associated with sigma(1) receptors. However, its pharmacological profile is partly distinct from those of selective sigma(1) receptor ligands. Thus, one of the possible speculations is that MS-377 has another site of action. In the present study, we examined the binding properties of radiolabeled MS-377 ([3H]MS-377) to rat brain membranes. [3H]MS-377 showed saturable and reversible binding to rat brain membranes. Scatchard plot and Hill plot from saturation studies were linear, with K(d) of 15.2+/-6.6 nM, B(max) of 599.4+/-58.6 fmol/mg protein and Hill coefficient of 1.01+/-0.01, indicating that [3H]MS-377 bound to a single high-affinity site in rat brain membranes. Displacement studies revealed that the other sigma reference compounds with different structures inhibited the specific binding of [3H]MS-377 in a competitive manner. Stereoselectivity was observed for the inhibition of [3H]MS-377 binding, (+)-isomers were more potent than (-)-isomers. Non-sigma receptor ligand PCP showed weak inhibition of [3H]MS-377 binding. The rank order of potency for the sigma reference compounds to displace [3H]MS-377 binding were as following: haloperidol>MS-377=(+)-pentazocine>DTG (1, 3-Ditolylguanidine)=(-)-pentazocine>BMY14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyramidinyl)-1-piperazine butanol)>(+)-SKF-10,047>(-)-SKF-10,047=PCP. These results suggested that the MS-377 selectively binds to sigma binding site with high affinity in rat brain membranes. Therefore, the anti-psychotic activities of MS-377 are attributable to association with sigma(1) receptors.
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PMID:Binding properties of [3H]MS-377, a novel sigma receptor ligand, to rat brain membranes. 1091 84


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