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)

Antipsychotics represent high affinity for sigma receptors and sigma-like drugs often have the psychotomimetic properties. Besides, the receptors are unevenly distributed in human brain. These findings suggest that sigma receptors might be involved in the pathophysiology of schizophrenia. Sigma receptors in rat and human brain were measured with [3H]-1, 3, di-o-tolylguanidine (DTG) and non-specific binding of [3H]DTG was determined in the presence of 10(-5)M haloperidol. Monovalent and divalent cations strongly inhibited [3H]DTG binding. Glutamate, aspartate and glycine also decreased the binding to human cerebral membranes. With post-mortem brain samples from 12 schizophrenics and 10 controls, sigma receptors were measured in 17 areas of cerebral cortex. Sigma receptors binding showed the regional differences in the cortex, but no significant differences between schizophrenics and controls were observed except the superior parietal cortex where the binding significantly increased in the schizophrenic group. These results suggest that sigma receptors in cerebral cortices might not be directly concerned with the pathophysiological role in schizophrenia.
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PMID:Sigma receptors in schizophrenic cerebral cortices. 132 40

Glutamate concentration was determined in serum from endogenous and neurotic depressive patients, in persons with schizophrenia or schizoaffective disorder, and in normal subjects. The mean serum glutamate level in the endogenous and neurotic depressive patients was found to be significantly higher than in any of the other groups. No other statistically significant differences were found. Statistical analysis revealed that the elevated serum glutamate concentration in the endogenous and neurotic depressive patients was probably caused by medication. These results are discussed in view of the effect of antidepressants upon the serum glutamate in the affective disorders.
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PMID:Increased serum glutamate in depressed patients. 613 11

In addition to the dopamine hypothesis, a glutamate hypothesis has been recently discussed in the biochemical theories on the cause of schizophrenia. In schizophrenic patients less glutamic acid has been found in the cerebrospinal fluid. Glutamate is probably the most important excitatory transmitter of the mammalian forebrain. The liberation of glutamic acid in the striatum is inhibited by dopamine, more specifically by the D2 receptor, which is also though to be responsible for the antipsychotic effects of neuroleptic drugs. It seems possible that schizophrenia may be primarily caused by underfunction of glutamatergic corticostriatal and corticomesolimbic neurons rather than by overfunction of the dopaminergic system. The negative cognitive symptoms associated with schizophrenia would fit in with this hypothesis. The classical and the new atypical neuroleptic drugs show differential effects on glutamate and GABA in the brain tissue of the striatum and in the cerebrospinal fluid. Whereas sulpiride diminishes glutamate in the striatum and enhances glutamate in the cerebrospinal fluid, tiapride does not affect either of them. Correspondingly, tiapride does not show any antipsychotic effects. Haloperidol, on the other hand, enhances the GABA level in the striatum in a dose-related manner. These findings may perhaps prompt experimental research to find antipsychotic drugs with fewer side effects.
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PMID:[A biochemical theory of schizophrenia]. 615 Nov 20

The influence of the medial prefrontal cortex (PFC) on mesolimbic dopamine activity was studied with electrophysiological techniques and in vivo voltammetry in the chloral hydrate-anesthetized male rat. Glutamate injected into the PFC selectively increased burst firing of single dopamine cells in the ventral tegmental area and enhanced the release of dopamine from nerve terminals in the nucleus accumbens. PFC injection of the local anesthetic lidocaine produced the opposite effects on burst firing and terminal release. This selective modulation of the dynamic activity of mesolimbic dopamine neurons by the prefrontal cortex might be important in motivation, learning and schizophrenia.
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PMID:Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo. 790 10

Excitatory amino acids (EAA) became known as neurotransmitters of the central nervous system (CNS) in the last decade. The most studied EAA are glutamate and aspartate. Both are synthetized by the same mechanism as gamaaminobutyric acid. (Fig. 1). Glutamate is widely distributed in the CNS and the spinal cord, being the areas of higher concentration the cerebral cortex, the hypocampus and the cerebellum. There have been identified two type of receptors for glutamate: ionotropic and metabotropic. The former includes three different types: NMDA, AMPA and KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the second ion the most important one. This receptor has several sites of binding for various substances. Along with the site for N-methyl-D-aspartate, which binds glutamate and/or aspartate, there have been identified a site for the binding of glycine (which is different from the strychnine sensitive one), a site for poliamines such as spermine and spermidine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is associated to a Ca(2+)-Na+ channel, being in this case the Na+ the most important ion. There are two metabotropic type receptors: L-AP4 and trans-ACPD. Both are coupled to a G protein and agonists exert their action increasing phospholipase C activity which in turn induces an increment of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ from intracellular stores. EAA play a role in some physiological processes. One of them is long-term potentiation (LTP), an electrochemical phenomenon involved in memory consolidation. Antagonists of NMDA and AMPA receptor prevent the development of LTP, and conversely, the agonist of glycine site of NMDA receptor--D-cycloserine--facilitates memory consolidation. Since 1957, EAA are considered neurotoxic substances and there are many indirect evidences to support this statement. Pathogenesis of neuronal damage elicited by EAA involves the events shown in Fig. 3. Prevention of the cascade of events that provokes neurotoxicity may be achieved by NMDA antagonists, but once it has begun it may be only aborted subtracting the Ca2+ from the medium, using nifedipine or blocking AMPA receptor with an antagonist (CNQX). EAA have been shown to play a toxic role in neuronal damage induced by ischemia. Research using various experimental models demonstrated that NMDA receptor antagonists (i.e. MK 801) blocks postischemic damage. Interventions at various levels of the pathogenic cascade shown in Fig. 4 provoke the same results. There is enough evidence to suspect that NMDA and AMPA receptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) prevent the development of epileptic seizures induced by kindling; CNQX, an AMPA antagonist, blocks the increase in electrical activity induced by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blocks the glycine site (not strychnine sensitive) decreasing NMDA receptor activity. Several neurodegenerative disorders have been associated with exogenous administration or accidental intake of EAA. (i.e. neurolatirism, Guam disease). Similarities between these diseases and lateral aminotrophic sclerosis indicate that in the latter EAA may play a pathogenic role. Finally, the psychotomimetic effect of phencyclidine (an antagonist of NMDA receptor) suggests that in schizophrenia, together with dopaminergic neurotransmission impairment, some dysfunction of glutamate pathways may be present.
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PMID:[Role of excitatory amino acids in neuropathology]. 872 78

Glutamate agonists have been shown to stimulate the release of dopamine in the striatum, while the NMDA receptor antagonist MK-801 has been shown to cause an increase in extracellular dopamine in the hippocampus. The effects of MK-801 treatment on dopamine receptor gene expression in the hippocampus are largely unknown. To begin to address this question, we treated rats with 0.3, 1.0, and 3.0 mg/kg of MK-801 daily for 1 week, and measured the mRNAs encoding all five of the dopamine receptors in the hippocampus. MK-801 caused changes in dopamine D1, D2, D3, and D4 receptor gene expression in a complex manner that suggests that dopamine receptor gene expression in the hippocampus may be differentially regulated by glutamate, via the NMDA receptor. These findings may have implications both for understanding the pathophysiology and modifying treatment of schizophrenia.
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PMID:Dopamine receptor gene expression in hippocampus is differentially regulated by the NMDA receptor antagonist MK-801. 881 39

Glutamate-containing neuronal terminals are ubiquitous in the central nervous system and their functional importance in mental activity is considerable. Therefore, the involvement of this neurotransmitter in the pathology of schizophrenia is being studied. Biochemical evidence has suggested that glutamatergic transmission may be regionally reduced in schizophrenia, although this evidence has never been completely consistent nor fully replicable. More striking has been the behavioral effects in humans of the antiglutamatergic drugs phencyclidine (PCP) and its congener ketamine. By historical report, PCP produces a 'schizophrenia-like' psychosis in normal humans and aggravates the psychosis in schizophrenics. More recently, ketamine has been shown to produce a mild psychotomimetic effect in normal volunteers, which has some schizophrenia-like features. We have studied the effects of ketamine in schizophrenic patients. Here, ketamine intensified each patient's specific underlying psychosis, an effect not blocked by haloperidol. Moreover, ketamine selectively increased cerebral blood flow (CBF) in the anterior cingulate cortex and reduced CBF in hippocampus and lingual gyrus. These data may be pertinent to the subject's psychosis exacerbation, especially because both cingulate and hippocampus have been previously implicated in schizophrenic psychosis. In addition, ketamine produced a distinctive dynamic time-course of regional CBF changes in different anatomic regions, with immediate (5-10 min) changes in cingulate, but somewhat more delayed changes (20-40 min) in the thalamus and cerebellum. Our immediate early gene (IEG) time-course data with c-fos and zif268 in rats following PCP suggest that a single dose of this antiglutamatergic compound can have an effect in some brain areas which lasts beyond 48 h, an effect which is distinct by IEG and by region. Together, these data suggest that glutamate-mediated neurotransmission has a strong influence in schizophrenia, although the specifics of this involvement have yet to be articulated.
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PMID:Glutamate pharmacology and the treatment of schizophrenia: current status and future directions. 886 63

Phencyclidine (PCP) induces a psychotic state closely resembling schizophrenia in normal individuals. PCP and related agents induce their unique behavioral effects by blocking neurotransmission mediated at N-methyl-D-aspartate (NMDA)-type glutamate receptors, indicating that dysfunction of NMDA receptor-mediated neurotransmission may play a crucial role in the pathophysiology of schizophrenia. NMDA receptors are activated by the amino acids glutamate and glycine, working at independent binding sites. Glutamate cannot be administered exogenously because of excitotoxicity. In contrast, glycine administered exogenously may potentiate NMDA receptor-mediated neurotransmission in vivo following peripheral administration. In rodents, glycine is effective in elevating brain glycine levels and reversing PCP-induced hyperactivity at doses of 0.8 g/kg and above. Three studies have now been completed utilizing moderate to high (0.4-0.8 g/kg/day) doses of glycine, added to neuroleptics, for the treatment of schizophrenia. Across studies, 15 to 30 percent improvement in negative symptoms was observed with no corresponding worsening of positive symptoms. Although preliminary, these studies indicate that dietary supplementation with glycine or treatment with other glycinergic agents may be effective in the treatment of schizophrenia.
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PMID:Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia. 899 96

structural abnormalities of the cerebral cortex in schizophrenia have been revealed by magnetic resonance imaging, although it is not clear whether these abnormalities are diffuse or local. We predicted that changes in cortical structure would result in abnormalities in biochemical markers for the glutamate system in post-mortem brain, and that the pattern of neurochemical abnormalities would be a clue to the distribution and extent of pathology. A number of studies have now reported increases in biochemical and other markers of glutamatergic cell bodies and terminals in the frontal cortex in schizophrenia. These findings are consistent with the presence of an abnormally abundant glutamatergic innervation, which may be due to an arrest in the normal developmental process of synaptic elimination. In the anterior temporal cortex and hippocampus there is evidence of an asymmetric loss of glutamate terminals, and of reduced GABA function, which may be secondary to the glutamatergic deficit. Glutamate cell body markers are spared in the temporal lobe; we argue that the loss of glutamate uptake sites may reflect the loss of an extrinsic glutamatergic innervation of the polar temporal cortex which arises from the frontal cortex. These fronto-temporal projections may be vulnerable because they arise from a cytoarchitecture which has not been stabilized by remodelling during early post-natal life. There have been several therapeutic studies of drugs with actions on brain glutamate systems. Based on the glutamate deficiency theories, one approach has been to enhance glutamatergic function using agonists of the N-methyl-D-aspartate-linked glycine site. However, there are no clear therapeutic effects, and some studies report aggravation of positive symptoms. This might be expected if, as part of our post-mortem studies suggested, there is excess glutamatergic innervation in some brain regions in schizophrenia. There is neuropsychological evidence that frontal abnormalities in schizophrenia may be genetically determined. We found that first degree relatives of schizophrenic patients were selectively impaired in tests of frontal lobe function, whereas both frontal and temporal function is impaired in patients We conclude that the genetic predisposition to schizophrenia involves impaired frontal lobe function. Psychotic symptoms develop only when a second process results in a loss of fronto-temporal projections and leads to temporal lobe dysfunction.
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PMID:Familial and developmental abnormalities of front lobe function and neurochemistry in schizophrenia. 925 79

Glutamate and GABA are the principle neurotransmitters of the cerebral cortex and are known to modulate dopaminergic function. Evidence of structural abnormalities in the cortex raises the possibility that schizophrenia involves disturbances of cortical amino-acid neurotransmission. The psychotomimetic effects of phencyclidine, a glutamate antagonist, have been taken to suggest that schizophrenia involves reduced brain glutamate function. Direct evidence for diminished glutamate function in schizophrenia is lacking. However, in polar temporal cortex and hippocampus we reported evidence of an asymmetric loss of glutamate terminals, and of reduced GABA function, which may be secondary to the loss of glutamatergic input. Glutamate cell body markers are spared in temporal lobe; the neurones which degenerate may originate in frontal cortex. A number of studies have reported increases in markers of glutamatergic cell bodies and terminals in orbital frontal cortex in schizophrenia. These findings are consistent with the presence of an abnormally abundant glutamatergic innervation, which may be the result of an arrest in the normal process of cellular and synaptic elimination which occurs during development. There is evidence that frontal abnormalities in schizophrenia are genetically determined. We suggest that glutamatergic abnormalities in anterior temporal cortex in schizophrenia are the result of the degeneration of fronto-temporal projections. Orbital frontal projections to polar temporal cortex may be prone to degeneration because they arise from an unstable frontal cortical cytoarchitecture which has not completed the normal process of post-natal remodelling. The structural abnormality of the orbital frontal region may confer vulnerability to some intrinsic or extrinsic mechanism, which brings about a progressive degeneration of projections to polar temporal lobe.
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PMID:A two-process theory of schizophrenia: evidence from studies in post-mortem brain. 927 90


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