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)

Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and beta-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered.
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PMID:Unconventional ligands and modulators of nicotinic receptors. 1243 14

The isoprenoid pathway produces digoxin, an endogenous membrane Na(+)-K+ ATPase inhibitor and regulator of neurotransmitter transport. The objective of the study was to relate digoxin status and hemispheric dominance to the pathogenesis of psychiatric disorders--bipolar mood disorder, major depressive disorder, and schizophrenia. The following parameters were assessed in bipolar mood disorder during the manic phase and depressive phase of the illness as well as in major depressive disorder, and schizophrenia: HMG CoA reductase activity, tryptophan and tyrosine catabolic patterns, red blood cell (RBC) Na(+)-K+ ATPase activity, and serum magnesium. These parameters were compared to individuals of differing hemispheric dominance. The levels of serum digoxin and HMG CoA reductase activity were found to be decreased in the depressive phase of bipolar mood disorder and major depressive disorder with a corresponding increase in RBC Na(+)-K+ ATPase activity and serum magnesium levels. There was increase in tyrosine and tyrosine catabolites, and a reduction in tryptophan and its catabolites, in the serum in the depressive phase of bipolar mood disorder and major depressive disorder. The neurotransmitter patterns and digoxin levels in the depressive phase of bipolar mood disorder/major depressive disorder correlated with those in right-handed/left hemisphere dominant individual. The neurotransmitter patterns and digoxin levels in the manic phase of bipolar mood disorder and schizophrenia correlated with those in left-handed/right hemisphere dominant individuals. Digoxin status and hemispheric dominance could correlate with the pathogenesis of psychiatric disorders--schizophrenia, major depressive disorder, and bipolar mood disorder.
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PMID:Membrane Na(+)-K+ ATPase mediated cascade in bipolar mood disorder, major depressive disorder, and schizophrenia--relationship to hemispheric dominance. 1244 37

A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome-X, rheumatoid arthritis and epilepsy has been described. The psychological behavioural patterns of the family were as follows--creativity and high IQ, hypersexual behaviour, reduced appetite and eating behaviour, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less of bonding and affectionate behaviour and left handedness. Digoxin, an endogenous Na(+)-K(+) ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na(+)-K(+) ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites - serotonin, quinolinic acid, strychnine and nicotine and decreased levels of hyperpolarising tyrosine catabolites dopamine, noradrenaline and morphine contributing to membrane Na(+)-K(+) ATPase inhibition in all the above disorders and the indexed family. Digoxin induced membrane Na(+)-K(+) ATPase inhibition can result in increased intracellular Ca(2+) and reduced Mg(++) levels leading to glutamate excitotoxicity, oncogene activation and immune activation. Digoxin induced altered Ca(++)/Mg(++) ratios, reduced ubiquinone and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure and mitochondrial function leading to the diverse disorders described above including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/left hemispheric dominant and left-handed/right hemispheric dominant individuals. The biochemical patterns in the indexed family and the diverse disorders studied correlated with those obtained in right hemispheric dominance. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and co-ordinate the functions of various cellular organelles.
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PMID:Hypothalamic digoxin--central role in conscious perception, neuroimmunoendocrine integration and coordination of cellular function--relation to hemispheric dominance. 1260 43

The membrane composition and the isoprenoid pathway metabolites important in maintaining cell membrane integrity was studied in neurological and psychiatric disorders. The results indicate alteration in cholesterol:phospholipid ratio of the RBC membrane which is increased in glioma, schizophrenia, and bipolar mood disorder (MDP); decreased in multiple sclerosis and Parkinson's disease; and not significantly altered in epilepsy. The concentration of total glycosaminoglycans (GAG), hexose, and fucose decreased in the RBC membrane and increased in the serum. The RBC membrane Na+-K+ ATPase activity was reduced and serum HMG CoA reductase activity was increased. There were increased serum levels of digoxin, cholesterol, and dolichol and decreased levels of ubiquinone. The serum magnesium and tyrosine levels were reduced and tryptophan increased. The results indicate a defect in membrane formation and a decreased membrane Na+-K+ ATPase activity in all the disorders studied. The results are discussed, and a hypothesis regarding the relationship between these disorders and defective membrane architecture and membrane Na+-K+ ATPase inhibition is presented.
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PMID:Isoprenoid pathway-related membrane dysfunction in neuropsychiatric disorders. 1458 55

Psychiatric abnormalities have been described in primary neurological disorders like multiple sclerosis, primary generalized epilepsy, Parkinson's disease, subacute sclerosing panencephalitis (SSPE), central nervous system glioma, and syndrome X with vascular dementia. It was therefore considered pertinent to compare monoamine neurotransmitter pattern in schizophrenia with those in the disorders described above. The end result of neurotransmission is changes in membrane Na(+)-K+ ATPase activity. Membrane Na(+)-K+ ATPase inhibition can lead to magnesium depletion, which can lead to an upregulated isoprenoid pathway. The isoprenoid pathway produces three important metabolites--digoxin, an endogenous membrane Na(+) -K+ ATPase inhibitor; ubiquinone, a membrane antioxidant and component of mitochondrial electron transport chain; and dolichol, important in N-glycosylation of protein. The serum/plasma levels of digoxin, dolichol, ubiquinone, magnesium, HMG CoA reductase activity, and RBC Na(+)-K+ ATPase activity were estimated in all these disorders. The result showed that the concentration of serum tryptophan and serotonin was high and serum tyrosine, dopamine, adrenaline, and noradrenaline low in all the disorders studied. The plasma HMG CoA reductase activity, serum digoxin, and serum dolichol levels were high and serum ubiquinone levels, serum magnesium, and RBC Na(+)-K+ ATPase activity were low in all the disorders studied. The significance of these changes in the pathogenesis of syndrome X, multiple sclerosis, primary generalized epilepsy, schizophrenia, SSPE, and Parkinson's disease is discussed in the setting of the interrelationship between these disorders documented in literature.
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PMID:Schizoid neurochemical pathology-induced membrane Na(+)-K+ ATPase inhibition in relation to neurological disorders. 1460 43

Amino acids play a role in neurotransmitter availability in the central nervous system, in that e.g. the synthesis of brain serotonin depends on the concentration of its precursor tryptophan. Disturbances in amino acid metabolism have been implicated in the pathophysiology of schizophrenia.In the present study the effect of a 14 week treatment with atypical antipsychotics on the plasma levels of amino acids was investigated in patients with schizophrenia and compared to normal controls.Non-responders (< or =20% decrease in BPRS at endpoint) demonstrated lower baseline values of methionine as compared to good responders (> or =50% decrease in BPRS at endpoint; p<.05) and controls (p<.01). The ratio between tryptophan and the other large neutral amino acids (Trp/LNAA ratio) in poor-responders (<40%) decreased during treatment as compared to responders (> or =40%; p<.05). It is concluded that poor or non-response to atypical antipsychotics may be associated with an impaired synthesis of serotonin in the central nervous system.
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PMID:Amino acids in schizophrenia: evidence for lower tryptophan availability during treatment with atypical antipsychotics? 1537 27

We investigated the effect of tryptophan depletion (tryptophan-free mixture) on locomotor activity in an animal model of schizophrenia, induced by acute administration of 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801), and the influence of the tryptophan-free mixture on the action of the typical antipsychotic haloperidol. Male rats were pre-treated with haloperidol 60 min after receiving the tryptophan-free mixture (or water). We measured total distance travelled in an open field during a 90-min period. Administration of the tryptophan-free mixture resulted in decreased levels of tryptophan, serotonin and its metabolite 5-hydroxyindolacetic acid in the frontal cortex. Serotonin depletion increased the total distance travelled by MK-801-treated rats, modified the inhibitory effect of haloperidol and normalized the locomotor activity pattern in the model of schizophrenia-like behaviour. The effect of the tryptophan-free mixture combined with the classical antipsychotic haloperidol in MK-801-treated rats indicates the possibly important role of the serotonergic system in the action of antipsychotics.
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PMID:The effect of tryptophan depletion on the action of haloperidol in MK-801-treated rats. 1546 96

Serotonin (5-hydroxytryptamine, 5-HT) is an amine neurotransmitter derived from tryptophan and is important in brain systems regulating mood, emotional behavior, and sleep. Selective serotonin reuptake inhibitor (SSRI) drugs are used to treat disorders such as depression, stress, eating disorders, autism, and schizophrenia. It is thought that these drugs act to prolong the action of 5-HT by blocking reuptake. This may lead to decreased 5-HT content in the nerve fibers themselves; however, this has not previously been directly demonstrated. We have studied the effects of administration of two drugs, imipramine and citalopram, on levels of 5-HT in nerve fibers in the murine brain. Quantitative analysis of the areal density of 5-HT fibers throughout the brain was performed using ImageJ software. While a high density of fibers was observed in mid- and hind-brain regions and areas such as thalamus and hypothalamus, densities were far lower in areas such as cortex, where SSRIs might be thought to exert their actions. As anticipated, imipramine and citalopram produced a decline in 5-HT levels in nerve fibers, but the result was not uniform. Areas such as inferior colliculus showed significant reduction whereas little, if any, change was observed in the adjacent superior colliculus. The reason for, and significance of, this regionality is unclear. It has been proposed that serotonin effects in the brain might be linked to changes in glutamatergic transmission. Extracellular glutamate levels are regulated primarily by glial glutamate transporters. Qualitative evaluation of glutamate transporter immunolabeling in cortex of control and drug-treated mice revealed no discernable difference in intensity of glutamate transporter immunoreactivity. These data suggest that changes in intracellular and extracellular levels of serotonin do not cause concomitant changes in astroglial glutamate transporter expression, and thus cannot represent a mechanism for the delayed efficacy of antidepressants when administered clinically.
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PMID:Quantitative analysis of immunolabeling for serotonin and for glutamate transporters after administration of imipramine and citalopram. 1585 94

The 5-hydroxytryptamine (5-HT, serotonin) system has been implicated in the pathophysiology and treatment of schizophrenia. In this study, we addressed the hypothesis that a deficit of 5-HT neurones, either inherited or acquired, is central to the developmental pathology of the disorder. We examined putative 5-HT neurones of the dorsal raphe nucleus (DRN) in post mortem, formalin-fixed tissue from 15 schizophrenic patients and 20 control subjects matched for age and gender. No significant difference was detected between these groups in the number or size (cross-sectional area or diameter) of tryptophan-hydroxylase-immunoreactive cell profiles viewed in transverse sections collected from the level of the trochlear decussation to the emergence of the trigeminal nerve. Profile number was not affected by age, gender, side of the brainstem (left or right) or post mortem interval; however, time in formalin correlated negatively with the number of neurones counted. Moreover, a significant negative correlation was detected between time in formalin and the levels of immunoreaction product (optical density), which in turn correlated positively with our profile counts. A positive correlation was found between the age of subjects and our estimates of cell size. Our results do not support the proposal that an abnormality in the number and/or size of DRN 5-HT neurones is central to the aetiopathology of schizophrenia.
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PMID:The dorsal raphe nucleus in schizophrenia: a post mortem study of 5-hydroxytryptamine neurones. 1588 63

Haloperidol is a high potency typical neuroleptic used in the treatment of schizophrenia. Administration of haloperidol produces muscles related side effects commonly known as extrapyramidal effects (EPS). These effects are not produced following the administration of atypical neuroleptics such as clozapine. A severe side effect of clozapine treatment is however, agranulocytosis. Development of antipsychotics with little/no EPS and/or other side effects is one of the exploring fields of drug research. This involves investigation on the mechanism by which a typical neuroleptic acting via serotonergic mechanism tends to produce less or no EPS. The present study is, therefore, designed to determine the effect of serotonin precursor tryptophan and a large neutral amino acid (valine) other than tryptophan on the modulation of neurochemical changes in the striatum. Neurochemical estimation were done by HPLC-EC. Present study showed that administration of tryptophan increased tryptophan, 5HT, 5HIAA and DA concentration in the striatum. DOPAC and HVA were not effected. Administration of valine increased DOPAC concentration in the striatum and did not alter tryptophan, 5HT, 5HIAA, DA and HVA concentration. Administration of the haloperidol increased HVA, 5HT and 5HIAA concentration. No effect was produced on tryptophan, DOPAC and DA levels. Valine administration followed by haloperidol injection did not alter striatal tryptophan, 5HT, DA, DOPAC and HVA concentration but decreased 5HIAA concentration. Administration of tryptophan followed by haloperidol injection increased tryptophan and 5HT concentrations and decreased DA levels. No effect was produced on 5HIAA, DOPAC and HVA concentrations. Administration of TRP increased plasma and brain concentration as well as DA levels in the striatum. Administration of valine did not decrease striatal TRP concentration while Haloperidol increased striatal 5-HT and 5-HIAA concentrations and no change in DA levels after haloperidol administration. whereas prior injection of TRP that increased 5HT concentration did not alter haloperidol-induced DA turnover in the brain.
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PMID:Effect of co administration of haloperidol and large neutral amino acids (tryptophan and valine) on rats striatal dopamine, serotonin and their metabolism. 1641 63


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