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)

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

The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds' balance can be observable in many disorders. It can be occur in neurodegenerative disorders, such as Parkinson's disease, Huntington's and Alzheimer's disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression. The increase of QUIN concentration or decrease of KYNA concentration could enhance the symptoms of several diseases. According to numerous studies, lowered KYNA level was found in patients with Parkinson's disease. It can be also noticeable that KYNA-treatment prevents against the QUIN-induced lesion of rat striatum in animal experiments. Administrating of KYNA can be appear a promising therapeutic approach, but its use is limited because of its poorly transport across the blood-brain barrier. The solution may be the development of KYNA analogues (e.g. glucoseamine-kynurenic acid) which can pass across this barrier and disengaging in the brain, then KYNA can exert its neuroprotective effects binding at the excitatory glutamate receptors, in particular the NMDA receptors. Furthermore, it seems hopeful to use kynurenine derivatives (e.g. 4-chloro-kynurenine) or enzyme inhibitors (e.g. Ro-61-8048) to ensure an increased kynurenic acid concentration in the central nervous system.
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PMID:Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies. 1701 44

The 2006 British Association for Psychopharmacology Summer Meeting was held in Oxford, UK. The British Association for Psychopharmacology is now one of the largest national psychopharmacology associations in the world with over 1000 members, and 550 national and international delegates attended the summer meeting. This meeting provides an annual forum for scientists and clinical investigators from academia and the pharmaceutical industry to share information on many aspects of the psychopharmacology of psychiatric illness. In total, 292 abstracts were accepted for presentation at the meeting. These were divided into 57 oral and 235 poster presentations. Research areas covered all aspects of psychopharmacology from basic research to pharmaceutical development and clinical application. This report highlights selected presentations from the meeting, focusing on rapid tryptophan depletion, which is a dietary manipulation that is used to study central serotonin function and putative animal models of depression and schizophrenia.
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PMID:British Association for Psychopharmacology Summer Meeting: 23-26 July 2006, Oxford, United Kingdom. 1702 Apr 26

This overview tries to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. Schizophrenia is a disorder of dopaminergic neurotransmission, but modulation of the dopaminergic system by glutamatergic neurotransmission seems to play a key role. This view is supported by genetic findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction, however, is mediated by the N-methyl-D-aspartate (NMDA)-receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYNA). Despite the NMDA receptor antagonism, KYNA also blocks, in lower doses, the nicotinergic acetycholine receptor, i.e., increased KYNA levels can explain psychotic symptoms and cognitive deterioration. KYNA levels are described to be higher in the cerebrospinal fluid (CSF) and in critical central nervous system (CNS) regions of schizophrenics as compared to controls. Another line of evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia. The type-1 response is partially inhibited, while the type-2 response is over-activated. This immune constellation is associated with inhibition of the enzyme indoleamine dioxygenase (IDO), because IDO - located in astrocytes and microglial cells - is inhibited by type-2 cytokines. IDO catalyzes the first step in tryptophan metabolism, the degradation from tryptophan to kynurenine, as does tryptophan 2,3-dioxygenase (TDO). Due to the inhibition of IDO, tryptophan-kynurenine is predominantly metabolized by TDO, which is located in astrocytes, not in microglial or other CNS cells. In schizophrenia, astrocytes in particular are activated, as increased levels of S100B appear. Additionally, they do not have the enzymatic equipment for the normal metabolism-route of tryptophan. Due to the lack of kynurenine hydroxylase (KYN-OHase) in astrocytes, KYNA accumulates in the CNS, while the metabolic pathway in microglial cells is blocked. Accordingly, an increase of TDO activity has been observed in critical CNS regions of schizophrenics. These mechanisms result in an accumulation of KYNA in critical CNS regions. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g., the use of anti-inflammatory cyclo-oxygenase-2 inhibitors, which can also decrease KYNA directly, are discussed.
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PMID:Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. 1706 75

Schizophrenia is associated with impairments of attentional control on classic experimental paradigms such as the Stroop task. However, at a basic level the neurochemical mechanisms that may be responsible for such impairments are poorly understood. In this study, we sought to investigate the influence of brain monoamine function on Stroop task performance in healthy participants using the established methods of acute dietary serotonin, dopamine, and combined monoamine depletion. The study was a double-blind placebo controlled design in which 12 healthy male participants completed the Stroop task under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Decreased Stroop interference indicating improved attentional control was observed after both tryptophan depletion and tyrosine/phenylalanine depletion, while there was no significant change in interference after combined monoamine depletion. Findings suggest that reduced tonic dopamine or serotonin activity within specific neural circuits (such as the striatum, anterior cingulate, or prefrontal cortex) may play a critical role in attentional control, possibly by improving gating of information via reducing noise in monoaminergic systems. These findings enhance our understanding of the neurochemical basis of attentional control and the possible cause of attentional control deficits in schizophrenia.
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PMID:Acute serotonin and dopamine depletion improves attentional control: findings from the stroop task. 1715 96


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