Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The dopamine hypothesis of schizophrenia proposes that schizophrenia is associated with increased brain dopaminergic function. Because dopamine is thought to stimulate the production of cyclic AMP in the brain, we hypothesized that CSF cyclic AMP would be increased in schizophrenia. Cyclic AMP in the CSF was determined in 19 schizophrenic patients who had not received neuroleptic treatment in the preceding two weeks. No significant difference could be shown between CSF cyclic AMP in these patients and CSF cyclic AMP in 10 psychiatrically normal controls.
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PMID:Cyclic AMP in the CSF of patients with schizophrenia. 18 6

Based on the results of studies on intracellular signaling in platelets of schizophrenics, an imbalance of the second messenger system is proposed: Diacylglycerol (DG), which activates protein kinase C (PKC), was increased, while adenylate cyclase (AC)-cAMP function was decreased. It is proposed that the increased DG/PKC function may entail a decrease in inositol 1,4,5-trisphosphate (IP3)/Ca2+ function and lowering of phosphoinositide turnover. If such a pathological intracellular signaling takes place in the brain, it may cause a distorted balance of protein activation via phosphorylation in neurons, resulting in some of the deficits of schizophrenia. Neuroleptics have been reported to antagonize the above-mentioned pathological processes of intracellular signaling. The imbalance hypothesis of the DG/PKC pathway and AC-cAMP pathway is not inconsistent with the dopamine hypothesis of schizophrenia, because dopamine receptor stimulation is indirectly related to reduction in IP3/Ca2+ function and lowering of phosphoinositide metabolism.
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PMID:Second messenger imbalance hypothesis of schizophrenia. 135 95

The results showed that the mean value of cAMP content in rats endbrain treated by electroacupuncture was obviously reduced than control group. The content of cAMP in the diencephalon and brain stem, the activity of Na(+)-K(+)-ATPase in the whole brain were raised and they show the positive relation with the excite intensity respectively. These experimental results might be taken as a basis for using the hand electroacupuncture for treatment of schizophrenia, manic state and depressive state. This experiment showed the treatment mechanisms of the hand electroacupuncture in accordance with ECT therapy.
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PMID:[Effects of hand electroacupuncture on the mean value of cAMP content and Na(+)-K(+)-ATPase activity in the tissue of various areas of the rat brain]. 216 26

The experiment adopted radioimmunoassay to assay CSF, platelets cAMP cGMP levels of a group of Schizophrenia patients, and made a correlation analysis between the cAMP, cGMP and the evaluated factor scores of BPRS and SCL-90. The results showed: (1)CSF cAMP level of Schizophrenics was significantly higher than normal controls; (2)There was a significantly positive correlation between CSF cAMP and BPRS factor 1, a significantly negative correlation between platelets cAMP and BPRS factor 3, a significantly positive correlation between CSF cAMP and SCL-90 factor 5,8. The paper discussed the similarities and differences between the results of this experiment and the former studies.
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PMID:[Assaying the SCF platelets cyclic nucleotides of schizophrenics and analyzing its correlation with pathopschological factors]. 217 85

Prostaglandin (PG) E1 enhances formation of 3H-adenosine-3',5'-cyclic monophasphate (3H-cAMP) in platelets pulse-labeled with 3H-adenine. This response was assessed as an index of receptor sensitivity and of PG function. Prostagladin E1-stimulated 3H-cAMP accumulation in paltelets from schizophrenics was significantly reduced compared with control subjects. Platelet incorporation of 3H-adenine and basal 3H-cAMP accumulation. We discuss the results in terms of the possible role of PGs in the etiopathology of schizophrenia and derivative implications for treatment.
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PMID:Prostaglandins, platelets, and schizophrenia. 625 71

1. Clinical observations and experimental findings are rendered which have raised the possibility that schizophrenia may be related to PGE deficiency and/or excess. 2. In favor of PGE1 deficiency are the findings that ADP-induced increase in synthesis and PGE1 stimulated cAMP accumulation are significantly lower in platelets of schizophrenic patients than in normal controls. 3. In favor of PGE excess are the findings that the concentration of immunoreactive PGE in cerebrospinal fluid of schizophrenics is higher than that of healthy controls, neurotic patients and patients undergoing neurological examination. 4. An argument against the PG excess hypothesis is that paracetamol, a substance which reduces PG levels has no therapeutic effect in schizophrenia. 5. The two hypotheses--PGE deficiency and PGE excess--are not compatible because of the bell shape dose response curve with PG's in certain biological systems.
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PMID:Prostaglandins and schizophrenia: a review. 628 32

Recently, increased brain and spinal fluid (CSF) norepinephrine (NE), and a decreased cAMP response to prostaglandin E1 (PgE1) stimulation of platelet NE sensitive adenylcyclase were observed in some schizophrenic patients. Low CSF dopamine-beta-hydroxylase (DBH) activity was related to brain atrophy, whereas high plasma DBH was associated with tardive dyskinesia. Increased NE (in brain and CSF) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels and decreased plasma DBH activity in the brain were associated with a diagnosis of paranoid schizophrenia. Impaired NE transmission in schizophrenia may relate to disturbances in the autonomic nervous system, deficits in attention and information processing and to an impaired ability to deal with stress. Although pharmacological studies have suggested a major role for dopamine (DA) in schizophrenic psychosis, this review indicates the need for further exploration of the NE system. Future studies should address the relationship with DA, the autonomic nervous system (ANS), cerebral blood flow, brain metabolism, stress response, negative and prodromal symptoms.
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PMID:Impaired noradrenergic transmission in schizophrenia? 632 3

As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetics of schizophrenia, GABAA receptor subunit genes are plausible candidate genes for the illness. We undertook a search for sequence variations in the coding region of beta 1 subunit gene by designing intron-based primers to amplify its 9 exons. Using single strand conformation polymorphism (SSCP) analysis, we found an exon 9 variant present in 3 of 86 unrelated schizophrenic cases derived from families having at least 2 first-degree relatives with schizophrenia. Direct sequencing of the SSCP variant revealed a C-->G nucleotide transversion at codon 396 predicting a histidine to glutamine substitution in the beta 1 peptide. The predicted amino acid substitution occurs at a highly conserved site, 9 residues from a cAMP-dependent serine phosphorylation consensus sequence. All known GABAA beta 1 subunit genes including human, bovine, and rat, code for histidine at position 396. Although the variant cosegregated with disease in a family with 2 affected sibs, it was only transmitted to 2 of 3 affected sibs in a multiplex family. The variant was not found in an additional sample comprising 155 unrelated schizophrenics and the sequence variant was present at a low frequency (approximately 1.1%) in control groups. Although these results indicate that the sequence variant is likely to be a natural polymorphism, it is possible that the variant may be a predisposing allele in rare instances. It is also possible that the variant may change the function or regulation of the GABAA receptor complex and it may be of pharmacogenetic relevance.
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PMID:Search for mutations in the beta 1 GABAA receptor subunit gene in patients with schizophrenia. 817 35

To search for possible alterations in second messenger systems in the temporal cortex (Brodmann's area 22) of patients with schizophrenia, we measured the binding activities of [3H]adenosine 3',5'-cyclic monophosphate ([3H]cAMP) and [3H]4 beta-phorbol 12,13-dibutyrate ([3H]PDBu) which can label the regulatory subunit of cAMP-dependent protein kinase (protein kinase A) and the regulatory domain of Ca2+/phospholipid-dependent protein kinase (protein kinase C), respectively. We also immunoquantified the variable subunits of guanine nucleotide binding proteins (G-proteins), using specific polyclonal antisera against Gs alpha, Gi alpha and Go alpha. Brains were obtained at autopsy on 10 patients with schizophrenia and 10 age-matched control subjects. Representative Scatchard plots for specific [3H]cAMP bindings to the soluble fraction consisted of a single component with high affinity (Kd = 2.36 nM, Bmax = 737 fmol/mg protein). Among the tested adenyl and guanyl nucleotides, or neuroleptics, cAMP alone potently inhibited the binding (Ki = 4.95 nM). The binding sites for [3H]cAMP were discretely localized, and were in the order of: cerebral cortex = hypothalamus = amygdala > hippocampus = neostriatum = thalamus = nucleus accumbens > globus pallidus = cerebellum. Specific [3H]cAMP bindings to the soluble fractions were about 30% greater in the left temporal cortices of schizophrenic patients, as compared to findings in the right side of the patients and the left side of the control subjects, no control brain showed this asymmetry. The specific [3H]PDBu binding in schizophrenic and control groups did not change.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increase in [3H]cAMP binding sites and decrease in Gi alpha and Go alpha immunoreactivities in left temporal cortices from patients with schizophrenia. 839 55

The human dopamine D2 receptor gene (DRD2) has three polymorphic variants that predict the amino acid substitutions Val96 --> Ala, Pro310 --> Ser, and Ser311 --> Cys in the receptor protein. We have investigated the ligand binding and signal transduction properties of these human D2 receptor variants by stably expressing them in cultured mammalian cells. The Cys311 and Ser310 variants of the human D2 receptor, which involve substitutions located in the third cytoplasmic loop, were markedly less effective in inhibiting cAMP synthesis than the most prevalent form (Pro310, Ser311). Despite this difference, the Cys311 and Ser310 variants couple to G proteins in CHO-K1 (Chinese hamster ovary) cells. The impairment of the Cys311 and Ser310 variants to inhibit cAMP levels thus appears to result from a reduced ability of those variant receptors to activate the appropriate Gi-like protein. The demonstration of substantial functional differences between DRD2 gene variants found in the human population might have important pharmacological implications given the widespread use of D2 receptor blocking drugs in the treatment of schizophrenia and other psychiatric disorders.
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PMID:Functional analysis of the human D2 dopamine receptor missense variants. 882 40


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