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)

Schizophrenia is a complex neuropsychiatric disorder in which symptoms can be classified as either positive, such as delusions and hallucinations, or negative, such as blunted affect and social withdrawal. However, the mechanisms underlying this disease are poorly understood. There is evidence that reactive oxygen species (ROS) play an important role in the pathogenesis of many diseases, particularly those which are neurological and psychiatric in nature. Ketamine has been used to induce a schizophrenia-like condition as an animal model in which to study this condition. In the present study we tested the effects of sub-anesthetic doses of ketamine on various parameters of oxidative stress in the brain of rats. Our results indicate that lipid peroxidation and tissue protein oxidation were affected by varying sub-anesthetic doses of ketamine in multiple cerebral structures. Additionally, the activity of the antioxidant enzymes CAT and SOD was measured and was also found to be altered in most of the structures tested. In conclusion, we observe an increase in oxidative damage marked by an increase in lipid peroxidation, oxidative protein damage and a decrease in enzymatic defenses, in an animal model of schizophrenia. Given that oxidative stress could be related to schizophrenia, these findings may explain, at least in part, the mechanisms underlying in this disease.
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PMID:Different sub-anesthetic doses of ketamine increase oxidative stress in the brain of rats. 1945 99

Schizophrenic patients show positive symptoms, negative symptoms and cognitive dysfunction. In humans, phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, reproduces the schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Ketamine, another non-competitive NMDA receptor antagonist, also reproduces a schizophrenia-like psychosis in healthy volunteers, and exaggerates the psychosis in schizophrenic patients. It has been hypothesized that insufficient glutamate neurotransmission is involved in the pathophysiology of schizophrenia. Therefore, attempts have been made to develop animal models of schizophrenia by using NMDA receptor antagonists such as PCP, ketamine and dizocilpine. In addition to pharmacological approaches, genetic approaches have been adopted to develop animal models of schizophrenia. The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, demonstrating that risk SNPs impact on the hippocampal structure and function in clinical and functional roles of DISC1 are analyzed in many kinds of transgenic mice developed. In this review, we focused on PCP and DISC1 transgenic animal models of schizophrenia and summarized recent evidence from several investigators. The basic researchers would need to collaborate with clinical psychiatrists to develop appropriate animal models for schizophrenia based on clinical evidence.
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PMID:[Development of animal models for schizophrenia based on clinical evidence: expectation for psychiatrists]. 1956 41

Altered neuroplasticity contributes to the pathophysiology of schizophrenia. However, the idea that antipsychotics may act, at least in part, by normalizing neurogenesis has not been consistently supported. Our study seeks to determine whether hippocampal cell proliferation is altered in adult rats pretreated with ketamine, a validated model of schizophrenia, and whether chronic administration with neuroleptic drugs (haloperidol and risperidone) affect changes of cell genesis/survival. Ketamine per se has no effect on cell proliferation. Its withdrawal, however, significantly induced cell proliferation/survival in the hippocampus. Risperidone and haloperidol supported cell genesis/survival as well. During ketamine withdrawal, however, their application did not affect cell proliferation/survival additionally. TUNEL staining indicated a cell-protective potency of both neuroleptics with respect to a ketamine-induced cell death. As RT-PCR and Western blot revealed that the treatment effects of risperidone and haloperidol seemed to be mediated through activation of VEGF and MMP2. The mRNA expression of NGF, BDNF, and NT3 was unaffected. From the respective receptors, only TrkA was enhanced when ketamine withdrawal was combined with risperidone or haloperidol. Risperidone also induced BCL-2. Ketamine withdrawal has no effect on the expression of VEGF, MMP2, or BCL-2. It activated the expression of BDNF. This effect was normalized by risperidone or haloperidol. The findings indicate a promoting effect of risperidone and haloperidol on survival of young neurons in the hippocampus by enhancing the expression of the anti-apoptotic protein BCL-2 and by activation of VEGF/MMP2, whereby an interference with ketamine and thus a priority role of the NMDA system was not evident.
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PMID:Risperidone and haloperidol promote survival of stem cells in the rat hippocampus. 1957

Ketamine, an N-methyl-D-aspartate (NMDA) receptor glutamatergic antagonist, has been studied as a model of schizophrenia when applied in subanesthetic doses. In EEG studies, ketamine affects sensory gating and alters the oscillatory characteristics of neuronal signals in a complex manner. We investigated the effects of ketamine on in vivo recordings from the CA3 region of mouse hippocampus referenced to the ipsilateral frontal sinus using a paired-click auditory gating paradigm. One issue of particular interest was elucidating the effect of ketamine on background network activity, poststimulus evoked and induced activity. We find that ketamine attenuates the theta frequency band in both background activity and in poststimulus evoked activity. Ketamine also disrupts a late, poststimulus theta power reduction seen in control recordings. In the gamma frequency range, ketamine enhances both background and evoked power, but decreases relative induced power. These findings support a role for NMDA receptors in mediating the balance between theta and gamma responses to sensory stimuli, with possible implications for dysfunction in schizophrenia.
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PMID:Ketamine modulates theta and gamma oscillations. 1958 75

Several electrical neural oscillatory abnormalities have been associated with schizophrenia, although the underlying mechanisms of these oscillatory problems are unclear. Animal studies suggest that one of the key mechanisms of neural oscillations is through glutamatergic regulation; therefore, neural oscillations may provide a valuable animal-clinical interface on studying glutamatergic dysfunction in schizophrenia. To identify glutamatergic control of neural oscillation relevant to human subjects, we studied the effects of ketamine, an N-methyl-D-aspartate antagonist that can mimic some clinical aspects of schizophrenia, on auditory-evoked neural oscillations using a paired-click paradigm. This was a double-blind, placebo-controlled, crossover study of ketamine vs saline infusion on 10 healthy subjects. Clinically, infusion of ketamine in subanesthetic dose significantly increased thought disorder, withdrawal-retardation, and dissociative symptoms. Ketamine significantly augmented high-frequency oscillations (gamma band at 40-85 Hz, p=0.006) and reduced low-frequency oscillations (delta band at 1-5 Hz, p<0.001) compared with placebo. Importantly, the combined effect of increased gamma and reduced delta frequency oscillations was significantly associated with more withdrawal-retardation symptoms experienced during ketamine administration (p=0.02). Ketamine also reduced gating of the theta-alpha (5-12 Hz) range oscillation, an effect that mimics previously described deficits in schizophrenia patients and their first-degree relatives. In conclusion, acute ketamine appeared to mimic some aspects of neural oscillatory deficits in schizophrenia, and showed an opposite effect on scalp-recorded gamma vs low-frequency oscillations. These electrical oscillatory indexes of subanesthetic ketamine can be potentially used to cross-examine glutamatergic pharmacological effects in translational animal and human studies.
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PMID:Gamma and delta neural oscillations and association with clinical symptoms under subanesthetic ketamine. 1989 Feb 62

Schizophrenia is one of the most important forms of psychiatric illness and may be chronic and highly disabling. It has been suggested that specific neurochemical abnormality is due to dopaminergic overactivity in the brain. Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute Phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. Administration of PCP or ketamine in rodents has been used to model aspects of schizophrenia. Taken into consideration the role of glutamatergic system in development of schizophrenia and involvement of striatal dopaminergic receptors in generation of schizophrenia symptoms, it was planned to study functional interaction between NMDA and metabotropic glutamatergic receptors 5 (mGluR5) in schizophrenia-associated behavioral and memory disturbance and the role of mGluRs allosteric modulation in cortico-striatal synaptic plasticity. In our experiments investigation of dose-dependent effects of ketamine revealed that 0.3mg/kg ketamine induces statistical changes most of behavioral and cognitive parameters in rats. Changes in emotional state showed decrease of the number and total duration of groomings in open field experiments as wall as in passive avoidance task. Decrease of motor activity was also detected, while no significant changes were observed in number of defecations. In T-maze test it was shown that spatial memory was damaged. To determine whether mGlu5 and NMDA receptor interact to regulate complex behaviors that are relevant to cognitive disorders such as schizophrenia we focused on assessing whether the selective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine MPEP mimics or exacerbates the effects of the NMDA receptor antagonist. Ketamine-induced memory disturbance was significantly increased after injection of mGluR5 negative allosteric modulators MPEP. In In vitro experiments the agonist at group I metabotropic glutamate receptors (mGluRI) (RS)-3,5-dihydroxyphenyl-glycine (DHPG,100 microM) evoked a persistent depression of the second component (N2) of the cortico-striatal field potential in rat slices. DHPG-induced plasticity was not NMDA-dependent. mGlu5 negative allosteric modulator MPEP diminishes the inhibition of synaptic responses induced by DHPG and completely blocked the late phase of depression. Our behavioral and in vitro data suggested that between NMDA and mGlu5 receptors there are functional interaction. Thus in some neurological or psychiatric disorders with NMDA dysfunction pharmacological manipulation of mGlu5 receptors could have therapeutic use.
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PMID:The role of the mGluR allosteric modulation in the NMDA-hypofunction model of schizophrenia. 2009 Jan 56

Glycine transporter inhibitors have recently been reported to improve symptoms in patients with schizophrenia. Here we used acute ketamine in the nonhuman primate to test the effectiveness of the novel glycine transporter inhibitor, PF-3463275, in a model of cognitive dysfunction relevant to schizophrenia. PF-3463275 (0.01-0.17 mg/kg; subcutaneously) or a vehicle was given before the administration of ketamine (median dose of 1.0 mg/kg intramuscularly) or placebo (saline). Ketamine induced hallucinatory-like behaviors that were not reversed by PF-3463275. In contrast, all doses of PF-3463275 alleviated the deficit in spatial working memory induced by ketamine. Theses findings build upon those in patients by providing translational support for targeting glycine transporter in adjunctive treatment for cognitive dysfunction in schizophrenia.
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PMID:Glycine transporter inhibition reverses ketamine-induced working memory deficits. 2018 6

The glutamatergic N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Administered to healthy volunteers, a subanesthetic dose of the non-competitive NMDA receptor antagonist ketamine leads to psychopathological symptoms similar to those observed in schizophrenia. In patients with schizophrenia, ketamine exacerbates the core symptoms of illness, supporting the hypothesis of a glutamatergic dysfunction. In a counterbalanced, placebo-controlled, double-blind study design, healthy subjects were administered a continuous subanesthetic S-ketamine infusion while differences in BOLD responses measured with fMRI were detected. During the scanning period, subjects performed continuous overt verbal fluency tasks (phonological, lexical and semantic). Ketamine-induced psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Ketamine elicited psychosis like psychopathology. Post-hoc t-tests revealed significant differences between placebo and ketamine for the amounts of words generated during lexical and semantic verbal fluency, while the phonological domain remained unaffected. Ketamine led to enhanced cortical activations in supramarginal and frontal brain regions for phonological and lexical verbal fluency, but not for semantic verbal fluency. Ketamine induces activation changes in healthy subjects similar to those observed in patients with schizophrenia, particularly in frontal and temporal brain regions. Our results provide further support for the hypothesis of an NMDA receptor dysfunction in the pathophysiology of schizophrenia.
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PMID:Neural correlates of S-ketamine induced psychosis during overt continuous verbal fluency. 2072 11

Schizophrenia is a debilitating mental disorder characterized by positive (delusions, hallucinations, disorganized speech) and negative (affective flattering, avolition, and social withdrawal) symptoms as well as cognitive deficits. The frequency, severity, and topography characterize the disorder as heterogeneous, the pathophysiology of schizophrenia is poorly understood. Sub-anesthetic doses of ketamine produce hyperactivity, stereotypy, and abnormal social interaction and it is used as a model of schizophrenia. In this study, we induced an animal model by acute sub-anesthetic doses of ketamine and tested different behavioral parameters. We also evaluated the activity of creatine kinase (CK) in brain of rats treated with ketamine. Our results demonstrated that administration of 10, 25 and 50 mg/kg of ketamine induced an increase of covered distance in habituated and non-habituated rats to the behavioral apparatus. Ketamine administration induced significant social deficits and stereotypic behavioral in all doses tested. Finally we evaluated the effect of different doses of ketamine on creatinine kinase (CK) activity and we observed that CK activity is increased inspecific regions of the brain. Our study suggests that our animal model may be used as a model of schizophrenia and that cerebral energy metabolism might be altered in the brain of schizophrenic patients, probably leading to alterations that might be involved in the pathogenesis of schizophrenia.
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PMID:A rodent model of schizophrenia reveals increase in creatine kinase activity with associated behavior changes. 2127 May 41

Neuroanatomical, electrophysiological and behavioural abnormalities following timed prenatal methylazoxymethanol acetate (MAM) treatment in rats model changes observed in schizophrenia. In particular, MAM treatment on gestational day 17 (E17) preferentially disrupts limbic-cortical circuits, and is a promising animal model of schizophrenia. The hypersensitivity of this model to the NMDA receptor antagonist-induced hyperactivity has been proposed to mimic the increase in sensitivity observed in schizophrenia patients following PCP and Ketamine administration. However, how this increase in sensitivity in both patients and animals translates to differences in EEG oscillatory activity is unknown. In this study we have shown that MAM-E17 treated animals have an increased response to the hyperlocomotor and wake promoting effects of Ketamine, PCP, and MK801 but not to the competitive antagonist SDZ 220,581. These behavioural changes were accompanied by altered EEG responses to the NMDAR antagonists, most evident in the gamma and high frequency (HFO) ranges; altered sensitivity of these neuronal network oscillations in MAM-exposed rats is regionally selective, and reflects altered interneuronal function in this neurodevelopmental model.
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PMID:Differential effects of NMDA antagonists on high frequency and gamma EEG oscillations in a neurodevelopmental model of schizophrenia. 2152 46


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