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)

In humans, repeated use of methamphetamine produces hypersensitivity to the psychotogenic effects of methamphetamine that persists for months to years after the discontinuation of methamphetamine administration. Methamphetamine-induced psychosis has been thought to be a useful experimental model for schizophrenia. A possible involvement of the glutamate system in the hypersensitivity including behavioral sensitization or reverse tolerance is recognized in an animal model for methamphetamine psychosis. We investigated the effects of antagonists of N-methyl-D-aspartate (NMDA) receptor on methamphetamine-induced decrease in dopamine (DA) uptake sites in the rat striatum and on the behavioral sensitization. Repeated administrations of escalating doses of methamphetamine (2.5, 5, 7.5, 10mg/kg s. c. x 2, every other day for a week) decreased DA uptake sites to about 75% of the control in the striatum assayed by binding with [3H]GBR 12935. Co-administration of MK-801, a non-competitive antagonist of NMDA receptor, and methamphetamine significantly prevented the methamphetamine-induced decrease in striatal [3H]GBR 12935 binding in a dose dependent manner. Administration of MK-801 alone did not affect the [3H]GBR 12935 binding. Furthermore, co-administration of SDZ EAA494, a competitive antagonist of NMDA receptor, and methamphetamine also prevented the methamphetamine-induced decrease in the striatal [3H]GBR 12935 binding in a dose dependent manner. In methamphetamine-pretreated rats, the methamphetamine challenge (2.5mg/kg) after a 7-day-drug-free period produced an initial elevation in locomotion lasting for 10-30 min which was followed by a precipitous drop in the locomotion activity to very low levels for approximately 50-70 min. During the period of reduced locomotor activity, methamphetamine-pretreated rats showed intense focused stereotyped behavior. In contrast, animals treated with both MK-801 and methamphetamine showed neither the progressive enhancement of the locomotor activity nor the stereotyped behavior induced by the drug. Pretreatment with MK-801 blocked the development of the methamphetamine-induced behavioral sensitization. These results suggest an involvement of excitatory amino acids in neurochemical effects of methamphetamine on the dopamine system in the striatum.
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PMID:[Effects of antagonists of NMDA receptor on methamphetamine-induced decrease in the dopamine uptake sites in the rat striatum and on the behavioral sensitization]. 831 37

The present study used in situ hybridization to c-fos mRNA to compare the effects of an 'ampakine' (a positive modulator of AMPA type glutamate receptors) with those of methamphetamine on the balance of aggregate neuronal activity in the cortex versus striatum. Methamphetamine (n = 11) induced a marked increase in c-fos mRNA in the dorsomedial quadrant of the striatum and a 21% smaller, but still reliable, increase in the ventrolateral quadrant. The drug also elevated c-fos mRNA levels in the ventral and medial segments of the orbitofrontal cortex but had no detectable effects in motor and somatosensory neocortices. The ampakine (n = 11) caused a near inverse pattern of changes; i.e. a sizable increase in somatosensory labeling and a significant decrease in striatal labeling with statistically insignificant effects in motor and orbitofrontal cortex. Within-rat cortical and striatal values were correlated in both the vehicle (n = 11) and ampakine groups, and appropriate comparisons established that the ampakine caused 27-55% increases in the ratio of cortical to striatal labeling. These results are in accord with the idea that facilitation of glutamatergic transmission has 'network level' effects that are opposite in nature to those resulting from enhanced dopaminergic transmission. The potential relevance of ampakines alone or in conjunction with dopamine antagonists for the treatment of schizophrenia is discussed.
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PMID:Comparison of the effects of an ampakine with those of methamphetamine on aggregate neuronal activity in cortex versus striatum. 919 Oct 86

Methamphetamine (METH) induces a schizophrenia-like psychosis. The dopamine neurons in the ventral tegmental area (VTA) have been implicated in schizophrenia and drug abuse. The present study investigated direct effects of METH on VTA dopamine neurons. We treated adult SD rats with METH (5 mg/kg/day) or saline for 7 days, isolated single VTA neurons, and monitored neuronal activities by measuring cytosolic Ca2+ concentration ([Ca2+]i) in immunocytochemically identified dopamine neurons. Acutely administered METH increased [Ca2+]i in dopamine neurons from METH- and saline-treated rats and induced oscillations of [Ca2+]i in dopamine neurons only from METH-treated rats. The METH-induced [Ca2+]i oscillations were inhibited by Ca(2+)-free conditions and Ca2+ channel blockers. The results indicate that acute METH increases [Ca2+]i in VTA dopamine neurons and that subchronic METH treatment sensitizes them to this drug, resulting in induction of [Ca2+]i oscillations. The activation of VTA dopamine neurons may be related to psycho-stimulant effects of METH.
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PMID:Methamphetamine induces cytosolic Ca2+ oscillations in the VTA dopamine neurons. 1079 Aug 82

The medial prefrontal cortex (PFC) is anatomically and functionally connected with the ventral tegmental area (VTA), the neuronal source of mesocorticolimbic system that is pathophysiologically related to schizophrenia-like symptoms. Methamphetamine (MAP) was applied to examine the functional relationship between PFC and VTA in an animal model of schizophrenia. Hyperactivity and stereotyped behavior were observed accompanied by a distinctive direction of information flow. In hyperactivity, information flow in the direction from PFC to VTA was dominant. Contrarily, dominant information flow from VTA to PFC was found in stereotyped behavior. These results indicate that dysfunctional interaction between PFC and VTA is the neuronal basis of MAP-induced schizophrenia-like psychosis. The information flow and its direction can be useful tool to explain the neurogenesis of these abnormal behaviors.
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PMID:Reciprocal information flow between prefrontal cortex and ventral tegmental area in an animal model of schizophrenia. 1088 61

Mesolimbic dopamine neurons in the ventral tegmental area (VTA), which project to the nucleus accumbens and prefrontal cortex, play an important role in the regulation of emotion, rewarding, and cognition. The dopamine neurons in the VTA have also been implicated in schizophrenia and drug abuse. Methamphetamine (METH) can induce a schizophrenia-like psychosis. Thus, the VTA is a likely effector site for the action of METH. However, effects of METH on the mesolimbic dopamine neurons are largely unknown. We treated adult SD rats with METH (5 mg/kg/day) or saline for 7 days, isolated single VTA neurons from these treated rats, and monitored the neuronal activities by measuring cytosolic Ca2+ concentration ([Ca2+]i), which was followed by immunocytochemical identification of dopamine neurons. Acute administration of METH under superfusion conditions concentration-dependently increased [Ca2+]i in VTA dopamine neurons isolated from METH- and saline-treated rats. Furthermore, acutely administered METH induced oscillations of [Ca2+]i only in the dopamine neurons of the METH-treated group. The METH-induced [Ca2+]i oscillations were inhibited by Ca2+-free conditions and by Ca2+ channel blockers. In conclusion, subchronic METH treatment sensitizes VTA dopamine neurons to this drug, resulting in induction of [Ca2+]i oscillations. This sensitization of VTA dopamine neurons may account, at least in part, for the psycho-stimulant effects of METH, such as the dependence on and sensitization to METH.
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PMID:Ca2+ oscillations in response to methamphetamine in dopamine neurons of the ventral tegmental area in rats subchronically treated with this drug. 1108 32

Over the last several years, Japan has been facing its third epidemic of methamphetamine abuse. Methamphetamine and MDMA are categorized as Amphetamine Type Stimulants (ATS), and abuse of these substances has become a worldwide problem. A nationwide mental hospital survey on substance-related psychiatric disorders in Japan has been conducted since 1987 to clarify the current situation of Japan's substance abuse and dependence. Recent surveys show that methamphetamine and organic solvents are the most common substances of abuse in hospital settings. Fifty-five percent of all the patients included in the latest study in 2002 had psychiatric disorders due to methamphetamine abuse. Forty-five percent of them were diagnosed as having a psychotic disorder, and twenty-five percent had psychotic episodes lasting over six months. According to the psychotic disorder criteria in ICD-10 (F1x.5), the duration of a psychotic episode must not exceed six months. If the criteria are strictly applied to the abusers, they should not be diagnosed as having a psychotic disorder due to methamphetamine use, but as having schizophrenia or some other delusional disorder. However, the study demonstrates that many psychiatrists in Japan recognize methamphetamine user patients with persistent episodes of psychosis as having psychosis due to the substance use. This may reflect differences of diagnostic viewpoint between operational criterion in English-speaking countries and clinical observation of Japanese psychiatrists. In other words, it may reflect the difference between the acute toxic model and chronic toxic model of substance-induced psychiatric disorders. Reconsidering this point further will be productive and interesting. The latest survey also indicated gender differences in psychiatric disorders related to substance use. It revealed that female patients were likely to have more severe dependence syndromes, co-morbid psychiatric disorders, and a history of traumatic life events. It suggests that the substance-related psychiatric problems in female patients are possibly more complex and harder to treat. Treatment programs that focus more on gender differences in these disorders should be developed.
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PMID:[Current situation of substance abuse/dependence in psychiatric hospital settings]. 1505 92

Schizophrenia resistant to treatments with D(2) antagonists is thought to have the changes of extradopaminergic systems. In addition, histamine has been suggested to be a neurotransmitter in the mammalian brain that regulates many brain functions. We have recently found evidence of the role of brain histamine in schizophrenia in basic and clinical studies. Methamphetamine-induced behavioral sensitization, which has been well established as the animal model of schizophrenia, induced the enhanced histamine release, and histamine agonists inhibited the development of behavioral sensitization. As another animal model of schizophrenia, phencyclidine also increased the histamine release. In clinical studies, the levels of N-tele-methylhistamine, a major brain histamine metabolite, were elevated in the cerebrospinal fluid of schizophrenics. Moreover, H(1) receptor binding sites decreased in schizophrenics. Many atypical antipsychotics also increased histamine turnovers. Therefore, the dysfunction of the histamine neuron system may participate in the extradopaminergic brain dysfunction of schizophrenia, and histamine agents may improve the refractory schizophrenia.
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PMID:The role of the central histaminergic system on schizophrenia. 1533 89

Methamphetamine (MAP), the most frequently abused substance in Japan, causes severe drug dependence and psychosis, similar to schizophrenia. It is suggested that long-term alterations in gene expression is related to MAP-induced brain dysfunction, including dependence and psychosis. DNA (cytosine-5) methyltransferase (Dnmt), a methylating enzyme of cytosine residues on CpG-dinucleotides, plays an important role in X chromosome inactivation, genomic imprinting, and gene expression. Reelin is an extracellular matrix protein secreted by GABAergic interneurons. Heterozygous reeler mice that exhibit a 50% downregulation of reelin expression replicate the dendritic spine and GABAergic defects described in schizophrenia. DNA methylation plays an important role in the epigenetic modification of reelin expression. We previously found that MAP could alter expression of Dnmt1 mRNA in the rat brain. In this study, we examined the brain mRNA for Dnmt2 and reelin in MAP-treated Wistar rats. Acute MAP (4 mg/kg) treatment significantly decreased Dnmt2 mRNA by 27% to 39% in hippocampus dentate gyrus, CA1, and CA3 24 h after treatment, and significantly decreased reelin mRNA by 28% in frontal cortex 3 h after treatment. These results suggest that (1) MAP can alter DNA methylation as well as expression of genes in these brain regions, and (2) decrease in reelin mRNA in the frontal cortex is similar to heterozygous reeler mice, which might be related to schizophrenia-like psychotic symptoms of MAP psychosis.
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PMID:Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain. 1554 6

Chromosome 3p was reported by previous studies as one of the regions showing strong evidence of linkage with schizophrenia. We performed a fine-mapping association study of a 6-Mb high-LD and gene-rich region on 3p in a Southern Chinese sample of 489 schizophrenia patients and 519 controls to search for susceptibility genes. In the initial screen, 4 SNPs out of the 144 tag SNPs genotyped were nominally significant (P < 0.05). One of the most significant SNPs (rs3732530, P = 0.0048) was a non-synonymous SNP in the neuroglycan C (NGC, also known as CSPG5) gene, which belongs to the neuregulin family. The gene prioritization program Endeavor ranked NGC 8th out of the 129 genes in the 6-Mb region and the highest among the genes within the same LD block. Further genotyping of NGC revealed 3 more SNPs to be nominally associated with schizophrenia. Three other genes (NRG1, ErbB3, ErbB4) involved in the neuregulin pathways were subsequently genotyped. Interaction analysis by multifactor dimensionality reduction (MDR) revealed a significant two-SNP interaction between NGC and NRG1 (P = 0.015) and three-SNP interactions between NRG1 and ErbB4 (P = 0.009). The gene NGC is exclusively expressed in the brain. It is implicated in neurodevelopment in rats and was previously shown to promote neurite outgrowth. Methamphetamine, a drug that may induce psychotic symptoms, was reported to alter the expression of NGC. Taken together, these results suggest that NGC may be a novel candidate gene, and neuregulin signaling pathways may play an important role in schizophrenia.
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PMID:Identification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population. 1936 81

Methamphetamine psychosis is considered as one of the pharmacological models of schizophrenia, and a hyperdopaminergic one. However, many lines of experimental evidence indicate that glutamatergic signaling is also involved in development of methamphetamine psychosis. Several genes related to glutamate function, e.g. the DTNBP1, G72, and GRM3 genes, were shown to be associated with schizophrenia susceptibility. Recently, we found significant association of the DTNBP1 gene with methamphetamine psychosis. This finding prompted us to examine the G72 gene encoding the d-amino acid oxidase activator (DAOA), which metabolizes d-serine, an NMDA co-agonist, in methamphetamine psychosis. Six SNPs of the G72 gene, which previously showed significant association with schizophrenia, were analyzed in 209 patients with methamphetamine psychosis and 291 age- and sex-matched normal controls. One SNP of M22 (rs778293) showed a significant association with methamphetamine psychosis (genotype: p=0.00016, allele: p=0.0015). Two haplotypes G-A of M12 (rs3916965)-M15 (rs2391191) (p=0.00024) and T-T of M23 (rs947267)-M24 (rs1421292) (p=0.00085) also showed associations with methamphetamine psychosis. The present findings suggest that the G72 gene may contribute to a predisposition to not only schizophrenia but also to methamphetamine psychosis.
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PMID:G72 gene is associated with susceptibility to methamphetamine psychosis. 1948 54


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