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)

sigma Receptors have been implicated in many pharmacological and physiological functions. sigma Receptors were purported to modulate behavioral alteration induced by cocaine and amphetamine, mediate effects of certain atypical antipsychotic agents, affect tonic potassium channels, the PCP/NMDA receptor complex, duodenal bicarbonate secretion, and CRF-induced colonic motility. sigma Receptors were reported to be altered in schizophrenia in certain studies, and up- and downregulations of sigma receptors have been observed in certain conditions. Neuropeptide Y has been shown to modulate the PCP/NMDA receptor complex in both central and gastrointestinal systems via sigma receptors. sigma Receptors are G-protein linked, and certain actions of sigma receptor ligands were affected by G-protein-modifying agents. Using photoaffinity labeling technique, a polypeptide of about 26 kDa has been identified as a sigma receptor. However, the exact biochemical relationship of this polypeptide to sigma receptors is unknown at present.
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PMID:Delineating biochemical and functional properties of sigma receptors: emerging concepts. 810 75

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

There is evidence for the existence of two classes of sigma binding sites, termed "site 1" and "site 2", that are distinct from opioid and PCP receptors. Sigma receptor ligands may be useful in the treatment of schizophrenia, since they improve not only positive but also negative symptoms with little extrapyramidal side effects in animal models. In addition, recent experiments have demonstrated that sigma receptor ligands attenuate the motor suppression and colonic motor disturbances seen under mentally stressful situations, stimulate the central cholinergic function thereby ameliorating impairment of learning and memory, and protect cerebral neurons against cerebral ischemic insult. The present review describes the neuropharmacological effects of sigma receptor ligands, especially anxiolytic (anti-stress) effects, ameliorating effects on impairment of learning and memory, and neuroprotective effects.
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PMID:[Neuropharmacological effects of sigma receptor ligands: anxiolytic, anti-amnesic and neuroprotective effects]. 890 94

The role of sigma (sigma) receptors in brain function is poorly defined. They are located in limbic areas, including nucleus accumbens (NAC) and prefrontal cortex (PFC), both of which are thought to be involved in schizophrenia. Many antipsychotics (APs), including haloperidol, bind with high affinity to sigma receptors. Dopaminergic hyperactivity in NAC is thought to underlie positive symptoms of schizophrenia, while dopaminergic hypoactivity in PFC is thought to underlie negative symptoms. Sigma receptors regulate N-methyl-D-aspartate (NMDA)-stimulated [3H] dopamine ([3H]DA) release in caudate-putamen (CP), the neuroanatomical substrate for extrapyramidal side effects resulting from chronic AP treatment. In the current study, we investigated whether sigma receptors could similarly regulate DA release in mesolimbic and mesocortical tissue, and the relative participation of different sigma receptor subtypes in this process. We found that, in NAC, regulation of DA release by the prototypical sigma agonist (+)pentazocine was mediated predominantly by the sigma 1 receptor, whereas in the PFC a portion of the (+)pentazocine effect was likely mediated by the sigma 2 receptor. We also observed, in both the NAC and PFC, that regulation of DA release by the sigma agonist BD737 was mediated primarily by the sigma 1 receptor. In addition, we determined that (+)pentazocine or BD737 effects on DA release were not mediated via opioid receptors, nor the phencyclidine (PCP) binding site within the NMDA receptor-operated cation channel, nor by sigma receptor effects upon [3H]DA accumulated by noradrenergic terminals in PFC.
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PMID:Regulation of [3H] dopamine release from mesolimbic and mesocortical areas of guinea pig brain by sigma receptors. 899 76

Until recently, racemic ketamine (S-ketamine/R-ketamine = 50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiological models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both positive and negative symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S)- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S)-ketamine binds with a 3-4 time higher affinity to the PCP binding site of the NMDA receptor than (R)-ketamine, and that at these concentrations (R)-ketamine interacts also weakly with the sigma receptor sites, where (S)-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure (S)- and (R)-ketamine enantiomeres on brain energy metabolism in normal humans using positron emission tomography and [18F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.
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PMID:Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). 908 82

Phencyclidine (PCP) can result in schizophrenia-like behavior. It binds at the PCP site on the NMDA-receptor calcium channel and at the sigma receptor. PCP also induces the heat shock gene hsp7O in retrosplenial cortex neurons. An antipsychotic drug, rimcazole, inhibits PCP hsp7O induction. Rimcazole binds predominantly to sigma-2 sites. It is hypothesized that sigma ligands without antipsychotic properties and with some sigma-2 affinity should partially reverse the effects of rimcazole. (+)-3-PPP, (+)-cyclazocine, and (+)-pentazocine bind predominantly to sigma-I sites. (+)-3-PPP is also a modest sigma-2 ligand. Female Sprague-Dawley rats (200-260 g) were injected intraperitoneally (IP) with (+)-3-PPP (50 mg/kg), rimcazole (60 mg/kg) and, after 5 min, with PCP (40 mg/kg). Brains were sectioned (100 mu m) and presence of the hsp7O gene protein product, HSP7O, was determined immunocytochemically. (+)-3-PPP significantly (0 <0.05) diminished the ability of rimcazole to inhibit PCP hsp7O induction in the retrosplenial cortex. (+)-Cyclazocine (15mg/kg, IP) and (+)-pentazocine (8Omg/kg, IP) given in an analogous manner did not diminish the ability of rimcazole to inhibit PCP hsp7O induction.
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PMID:Effects of sigma ligands on the ability of rimcazole to inhibit PCP hsp70 induction. 913 45

Phencyclidine (PCP) is a compound that results in abnormal human behavior and has been proposed as a chemical model for schizophrenia. It was hypothesized that PCP induction of the immediate-early gene, c-fos, should be seen in areas associated with emotional behavior, such as the cortex and limbic system. It was also proposed that PCP may induce c-fos via the sigma receptor. PCP and two sigma ligands, 1,3-di(2-tolyl)guanidine (DTG) and pentazocine, were shown to induce c-fos in similar patterns. The three compounds abundantly induced c-fos in the cingulate, parietal, and piriform cortices and the midline structures of the thalamus and hypothalamus. Neither PCP nor the sigma ligands induced c-fos in the hippocampus. This suggests that PCP binding at NMDA receptors does not result in significant c-fos induction. Rimcazole, a putative sigma2 receptor antagonist, and other sigma ligands have been shown to ameliorate PCP stereotypic behavior. Rimcazole inhibited PCP c-fos induction in the cingulate and parietal cortices and DTG c-fos induction in the cingulate cortex. DTG shows both sigma1 and sigma2 binding affinity. Rimcazole failed to inhibit pentazocine c-fos induction. Pentazocine binds only to sigma1 receptors. This suggests that PCP may produce a significant fraction of its c-fos induction via sigma2 receptors.
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PMID:Phencyclidine (PCP) acts at sigma sites to induce c-fos gene expression. 920 33

Several antipsychotic agents such as haloperidol and rimcazole are known to bind to sigma receptors with high affinity, and evidence for a potential link between sigma receptors and the etiology of schizophrenia has been reported. The present study was conducted to systematically search for nucleotide variants of the type 1 sigma receptor gene in 48 schizophrenics. Two polymorphisms were found: GC-241-240TT in the 5' flanking region and Gln2Pro. These two polymorphisms were in nearly complete linkage disequilibrium with each other. The Pro2 variant of the Gln2Pro polymorphism changes the endoplasmic reticulum retention signal motif. These polymorphisms were examined in an extended sample of schizophrenics (n = 308) and controls (n = 433) and a significant association between the presence of the TT/Pro2 haplotype and schizophrenia was observed (odds ratio = 1.27, P = 0.04).
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PMID:Association between polymorphisms in the type 1 sigma receptor gene and schizophrenia. 985 62

EMD 57455 (panamesine) is a new sigma receptor ligand alleged to have antipsychotic effects. Animal studies have demonstrated that EMD 57445 has a functional antidopaminergic activity without extrapyramidal side effects and a c-fos expression pattern similar to that obtained with atypical neuroleptics. Therefore, the substance might be of interest for the treatment of schizophrenia. The present article describes the results of an exploratory open clinical trial that was aimed at determining the appropriate dose range for clinical efficacy and safety of EMD 57455 in patients with an acute episode of schizophrenia. In a treatment period of 4 weeks, 12 patients received EMD 57445 up to 60 mg/day for 4 weeks. Seven patients completed the study: four were classified as responders (as defined by at least a 50% decrease in the BPRS total score), two improved slightly and one patient remained unimproved. The intent-to-treat analysis showed significant improvement in the psychometric variables assessed by the Brief Psychiatric Rating Scale, Clinical Global Impression and Positive and Negative Symptoms Scale. Major side effects were extrapyramidal symptoms in two patients and restlessness in one patient. With respect to efficacy and safety, our data agree with a previous study, except that in our study EMD 57455 was not totally free of extrapyramidal side effects.
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PMID:Efficacy and safety of the sigma receptor ligand EMD 57445 (panamesine) in patients with schizophrenia: an open clinical trial. 1033 65

Studies on the sigma receptor and related compounds are becoming more attractive since they were found to be closely related to higher brain functions such as memory, learning, depression, anxiety, schizophrenia and neuroprotection. Along with these pharmacological findings, the single transmembrane-type, non-metabotropic sigma binding protein has been cloned, while the presence of metabotropic sigma receptor has been also claimed. Thus, various pharmacological findings are now ready to be characterized on the molecular basis of receptor mechanisms. On the other hand, neurosteroids have higher brain functions such as non-genomic fast actions, which are similar to the actions of sigma compounds. Indeed some neurosteroids were revealed to behave as sigma agonists while others behave like antagonists of metabotropic sigma receptors. Pharmacological studies to determine if sigma compounds can be used to cure various central symptoms related to neurosteroids or steroid hormones can be expected.
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PMID:[Sigma (sigma) receptor and neurosteroids]. 1056 65


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