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)

Glutamic acid levels were investigated in the cerebrospinal fluid and blood serum of patients with schizophrenia, Huntington's chorea, and sciatic nerve compression by lumbar disc protrusion. In the serum the glutamic acid levels were equal in all three groups; in the cerebrospinal fluid (CSF) of schizophrenic and Hungtington's patients, however, the glutamic acid was decreased to almost half that of the lumbar disc group which served as control. Most of the patients were treated with neuroleptic drugs. However, since in one case (the daughter of a Huntington's patient) the CSF glutamic acid was decreased although this woman had had no neuroleptic treatment, it seems more likely that the glutamic acid decrease is due to the disease rather than to the neuroleptic treatment.
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PMID:Reduction of cerebrospinal fluid glutamic acid in Huntington's chorea and in schizophrenic patients. 610 77

A recently proposed hypothesis to explain schizophrenia is based on reports of reduced concentrations of glutamic acid in the cerebrospinal fluid (CFS) of schizophrenic patients. This hypothesis suggests that there may be a dysfunction of glutamatergic neurons in schizophrenia, with either a degeneration of these neurons, or their failure to release glutamate as a neurotransmitter. Direct measurement of glutamate levels in CSF and autopsied brain of schizophrenic patient showed no differences from glutamate levels in suitable adult control subjects. The data presented here do not offer support for the new hypothesis.
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PMID:Normal cerebrospinal fluid and brain glutamate levels in schizophrenia do not support the hypothesis of glutamatergic neuronal dysfunction. 612 7

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 glutamate antagonist glutamic acid diethyl ester is found to produce catalepsy in rats, when administered into the lateral ventricle. Since the cerebrospinal fluid content of glutamate is reduced in patients with schizophrenia, the central effects of glutamate antagonists are a possible experimental model for schizophrenia.
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PMID:Glutamic acid diethyl ester induces catalepsy in rats. A new model for schizophrenia? 689 56

Using an enzyme-linked immunosorbent assay, significantly raised concentrations of immunoglobulin G with affinity for the neurotransmitter dopamine were demonstrated in cerebrospinal fluid from psychotic patients. We have varied the antigen presentation in order to find a conjugate with low unspecific binding. The conjugation of dopamine to carbodiimide-activated poly-L-glutamic acid and that to activated succinimide ester of biotin are described. The use of glutaraldehyde conjugation is not recommended because of the risk of formation of tetrahydroisoquinolines. A strong correlation (r = 0.94, P < 0.001) between the results obtained with dopamine conjugated to poly-L-glutamic acid and dopamine conjugated to biotin was observed. Forty-two human cerebrospinal fluid samples from 20 psychotic patients, (12 with a bipolar disorder and 8 with schizophrenia) and 22 control patients, with various neurological diseases but no apparent psychiatric diseases were investigated. A significantly higher incidence (P < 0.001) of antibodies with affinity for dopamine were found in the group of psychotic patients compared with the neurological control group.
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PMID:Demonstration of immunoglobulin G with affinity for dopamine in cerebrospinal fluid from psychotic patients. 826 22

Glutamic acid is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Specific receptors bind glutamate and some of these when activated open an integral ion channel and are thus known as ionotropic receptors. Within the ionotropic family of glutamate receptors, three major subtypes have been identified using classical specific agonist activation, selective competitive antagonists together with their structural heterogeneity. These receptors have thus been named N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate receptors. The NMDA receptor has sites in addition to its agonist-binding site and these seem to either positively or negatively modulate the agonist effect. The NMDA receptor also is unique in that another amino acid, glycine, acts as a co-agonist with glutamate. Changes in glutamate transmission have been associated with a number of CNS pathologies; these include, acute stroke, chronic neurodegeneration, chronic pain, depression, drug dependency, epilepsy, Parkinson's Disease and schizophrenia.
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PMID:Excitatory amino acid agonists and antagonists: pharmacology and therapeutic applications. 1081 62

In this review, we will first present a brief overview of the current understanding of: (a) the biology of reelin; (b) the putative reelin signaling pathways via integrin receptor stimulation; (c) the cytosolic adapter protein DAB1, which appears to be operative in the transduction of reelin's pleiotropic actions in embryonic, adolescent, and adult brain; (d) the regulation of GABAergic function, including some aspects of GABAergic system development; and (e) dendritic spine function and its role in the regulation of synaptic plasticity. We argue that a downregulation of reelin expression occurring in prefrontal cortex and in every brain structure of schizophrenia patients so far studied may be associated with a decrease in dendritic spine expression that in turn may provide an important reduction of cortical function as documented by the downregulation of glutamic acid decarboxylase67 (GAD67) expression, which might be secondary to a reduction of GABAergic axon terminals. This hypothesis is supported by a genetic mouse model of reelin haploinsufficiency that replicates the above-described dendritic and presynaptic GABAergic defects documented in schizophrenia brains.
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PMID:Dendritic spine hypoplasticity and downregulation of reelin and GABAergic tone in schizophrenia vulnerability. 1159 44

Although the etiology of drug psychosis or schizophrenia is still unknown, molecular and biochemical researches have recently made significant advances in the search for the candidate genes of these disorders. Among such studies are animal models of drug psychosis or schizophrenia such as amphetamine-induced behavioral sensitization or phencyclidine-treated animals. In this review, it is suggested that amphetamine or phencyclidine change the gene expressions related to not only neurotransmitter systems such as dopamine or glutamic acid, transcription factors, cell proliferation, apoptosis, cell adhesion, but also the synapse. These alterable gene expressions may lead to the discovery of candidate genes of drug psychosis or schizophrenia and thus to novel antipsychotics.
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PMID:Analysis of overall gene expression induced by amphetamine and phencyclidine: novel targets for the treatment of drug psychosis and schizophrenia. 1181 56

gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA is converted from glutamic acid by the action of glutamic acid decarboxylase (GAD) of which two isoforms exist GAD65 and GAD67. GABA then is broken down, both within the cell and in the synaptic cleft by GABA transaminase to form succinic semialdehyde. In turn, succinic semialdehyde is converted either to succinic acid by succinic semialdehyde dehydrogenase or into gamma-hydroxybutyric acid (GHB) by succinic semialdehyde reductase. Because GABA modulates the majority of inhibition that is ongoing in the brain, perturbations in GABAergic inhibition have the potential to result in seizures. Therefore, the most common disorder in which GABA is targeted as a treatment is epilepsy. However, other disorders such as psychiatric disease, spasticity, and stiff-person syndrome all have been related to disorders of GABAergic function in the brain. This review covers the roles of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, stiff-person syndrome, and premenstrual dysphoric disorder. In the final section of this review, the GABA metabolite GHB is discussed in terms of its physiological significance and its role in epilepsy, sleep disorders, drug and alcohol addiction, and an inborn error of GABA metabolism, succinic semialdehyde dehydrogenase deficiency.
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PMID:GABA, gamma-hydroxybutyric acid, and neurological disease. 1289 48

L-Glutamate serves as a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and is stored in synaptic vesicles by an uptake system that is dependent on the proton electrochemical gradient (VGLUTs). Following its exocytotic release, glutamate activates fast-acting, excitatory ionotropic receptors and slower-acting metabotropic receptors to mediate neurotransmission. Na+-dependent glutamate transporters (EAATs) located on the plasma membrane of neurons and glial cells rapidly terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels. Thus far, five Na+-dependent glutamate transporters (EAATs 1-5) and three vesicular glutamate transporters (VGLUTs 1-3) have been identified. Examination of EAATs and VGLUTs in brain preparations and by heterologous expression of the various cloned subtypes shows these two transporter families differ in many of their functional properties including substrate specificity and ion requirements. Alterations in the function and/or expression of these carriers have been implicated in a range of psychiatric and neurological disorders. EAATs have been implicated in cerebral stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, Huntington's disease, amyotrophic lateral sclerosis (ALS) and malignant glioma, while VGLUTs have been implicated in schizophrenia. To examine the physiological role of glutamate transporters in more detail, several classes of transportable and non-transportable inhibitors have been developed, many of which are derivatives of the natural amino acids, aspartate and glutamate. This review summarizes the development of these indispensable pharmacological tools, which have been critical to our understanding of normal and abnormal synaptic transmission.
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PMID:Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. 1521 Mar 7


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