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)

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

Development of antipsychotics with slight/no extra-pyramidal symptoms (EPS) and/or other side effects is one of the exploring fields of drug research. Haloperidol is a high potency typical neuroleptic used in the treatment of schizophrenia but produces muscles related side effects commonly known as 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. 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 was, therefore, designed to determine the effect of serotonin precursor tryptophan and a large neutral amino acid other than tryptophan (valine) on the modulation of haloperidol induced catalepsy and akinesia. Cataleptic effects of the drug and activity reducing effects were monitored on inclined surface and in an activity box or open field respectively. The results are discussed in the context of a role of tryptophan and valine induced changes of brain serotonin in modifying the extrapyramidal and monoaminergic effects of the typical neuroleptic haloperidol. In the present study administration of TRP and valine decreased activity in rats, haloperidol-induced catalepsy' was not modulated by prior administration of tryptophan or valine. Brain serotonin levels were elevated by haloperidol treatment and correlated very well with the behavioral response. These findings suggest a possible serotonergic involvement in neuroleptic induced tardive dyskinesia and an amelioration of the disorder through TRP supplementation.
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PMID:Effects of tryptophan and valine administration on behavioral pharmacology of haloperidol. 1643 94

The brain and cerebrospinal fluid levels of kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation and antagonist of the glycine(B) receptor and the alpha7 nicotinic acetylcholine receptor, are elevated in persons with schizophrenia. To evaluate whether this increase is related to antipsychotic medication, we examined the effects of haloperidol (HAL), clozapine (CLOZ) or raclopride (RAC) on brain KYNA levels in rats. Animals received either acute drug injections or ingested the drugs chronically with the drinking water. Acute application or one-week drug exposure had no effect on brain KYNA levels. After one month, HAL, CLOZ and RAC all caused significant reductions in KYNA levels in striatum, hippocampus and frontal cortex. Quantitatively similar reductions in the brain tissue content of KYNA were observed after one year of HAL administration. All these effects were accompanied by equivalent decreases in the extracellular concentration of KYNA, measured by striatal microdialysis. Separate animals received an intrastriatal infusion of (3)H-kynurenine to probe the entire kynurenine pathway acutely in rats treated with HAL for one year. These animals showed reduced (3)H-KYNA production, but no changes in the formation of other kynurenine pathway metabolites. By enhancing glutamatergic and cholinergic neurotransmission, reduced brain KYNA levels may play a role in the clinical effects of prolonged antipsychotic medication.
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PMID:Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain. 1646 54

Kynurenic acid (KYNA) is a tryptophan metabolite synthesized and released by glia and recently shown to be a non-competitive antagonist of alpha7 nicotinic acetylcholine receptors at physiologically relevant concentrations, and NMDA receptors at higher concentrations. KYNA concentration is elevated in individuals with schizophrenia and those with Alzheimer's disease, two populations exhibiting cholinergic-related cognitive impairments. The present study investigated the effects of elevated KYNA concentration on conditioned stimulus processing in rats. For the first 2 days of the experiment, a subset of rats received intracerebroventricular infusions of either KYNA (0.1 microM) or vehicle and were either returned to the home cage or received non-reinforced presentations of a visual stimulus. All rats subsequently received presentations of the same visual stimulus followed by food reward during a 6-day training phase. In vehicle-treated rats, pre-exposure to the visual stimulus reduced orienting behaviour to the light (standing on the hind legs and orienting towards the visual stimulus) when it was later reinforced (i.e., conditioned orienting). In contrast, pre-exposure to the visual cue or 2 days of KYNA pretreatment reduced conditioned orienting behaviour. Finally, the reduction of orienting in KYNA-treated rats following pre-exposure was not as robust as in vehicle-treated rats. These results suggest that elevated KYNA levels can alter specific aspects of attentional processing of environmental stimuli and are discussed in terms of the potential contribution of KYNA to cognitive function and dysfunction.
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PMID:Increased concentration of cerebral kynurenic acid alters stimulus processing and conditioned responding. 1662 Oct 49

This review focuses on possible causes and the impact of different immune states in schizophrenia and major depression. It discusses the fact that, in schizophrenia, an over-activation of the type 2 immune response may dominate, while the type 1 and the pro-inflammatory immune responses are over-activated in major depression. The consequence of these diverse immune states is the activation and, respectively, inhibition of different enzymes in tryptophan/kynurenine metabolism, which may lead to an overemphasis of N-methyl-D-aspartate (NMDA) receptor antagonism in schizophrenia and of NMDA-receptor agonism in depression, resulting in glutamatergic hypofunction in schizophrenia and glutamatergic hyperfunction in major depression. In addition, the activation of the type 1 and the pro-inflammatory immune responses in major depression result in increased serotonin degradation and a serotonergic deficit. While antipsychotics and antidepressants today mainly act on the dopaminergic-glutamatergic and the noradrenergic-serotonergic neurotransmission, anti-inflammatory and immune-modulating therapies might act more basically at the pathophysiological mechanism. The limitations of this concept, however, are critically discussed.
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PMID:Neuroimmune-endocrine crosstalk in schizophrenia and mood disorders. 1683 Nov 16

This manuscript deals with whether immune-mediated mechanisms of inflammation contribute to the pathogenesis of schizophrenia. A model is presented which integrates psychoneuroimmunologic findings and actual results from pharmacological, neurochemical, and genetic studies in schizophrenia. A pivotal role in the neurobiology of schizophrenia is played by dopaminergic neurotransmission, which is modulated by influences of the glutamatergic system. The decreased function of the glutamate system described in schizophrenia seems primarily mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. Kynurenine acid is the only known endogenous NMDA receptor antagonist. In higher concentrations it blocks the NMDA receptor, but in lower concentrations it blocks the nicotinergic acetylcholin receptor, which has a prominent role in cognitive functions. Therefore, higher levels of kynurenine acid may explain psychotic symptoms and cognitive dysfunction. Several findings point out that prenatal infection, associated with an early sensitisation of the immune system, may result in an imbalance of the immune response (type 1 vs type 2) in schizophrenia. This immune constellation leads to inhibition of the enzyme indoleamin dioxigenase (IDO). It and tryptophane 2,3-dioxygenase (TDO) both catalyse the degradation from tryptophan to kynurenine. Due to the inhibition of IDO, tryptophan is metabolised to kynurenine primarily by TDO. In the CNS, TDO is located only in astrocytes, which are in particular activated in schizophrenia and in which kynurenine acid is the final product and can not be further metabolised. Therefore kynurenine acid accumulates in the CNS of schizophrenics and - due to its NMDA-antagonistic properties - leads to cognitive dysfunction and psychotic symptoms. This model describes the pathway of immune-mediated glutamatergic-dopaminergic dysregulation, which may lead to the clinical symptoms of schizophrenia. Therapeutic consequences (e.g. cyclo-oxygenase-2 inhibitors) are discussed.
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PMID:[Immunology in schizophrenic disorders]. 1689 51

Kynurenic acid (KYNA) is a tryptophan metabolite that is synthesized and released by astrocytes and acts as a competitive antagonist of the glycine site of N-methyl-D-aspartate receptors at high concentrations and as a noncompetitive antagonist of the alpha7-nicotinic acetylcholine receptor at low concentrations. The discovery of increased cortical KYNA levels in schizophrenia prompted the hypothesis that elevated KYNA concentration may underlie the working memory dysfunction observed in this population that has been attributed to altered glutamatergic and/or cholinergic transmission. The present study investigated the effect of elevated endogenous KYNA on spatial working memory function in rats. Increased KYNA levels were achieved with intraperitoneal administration of kynurenine (100 mg/kg), the precursor of KYNA synthesis. Rats were treated with either kynurenine or a vehicle solution prior to testing in a radial arm maze task at various delays. Elevations of endogenous KYNA resulted in increased errors in the radial arm maze. In separate experiments, assessment of locomotor activity in an open field and latency to retrieve food reward from one of the maze arms ruled out the possibility that deficits in the maze were attributable to altered locomotor activity or motivation to consume food. These results provide evidence that increased KYNA levels produce spatial working memory deficits and are among the first to demonstrate the influence of glia-derived molecules on cognitive function. The implications for psychopathological conditions such as schizophrenia are discussed.
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PMID:Elevations of endogenous kynurenic acid produce spatial working memory deficits. 1692 Jul 87


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