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)

Phencyclidine has frequently been used to model schizophrenia in animals. In the present study, the ability of the neuronal selective nitric oxide synthase (NOS) inhibitor, Nomega-propyl-L-arginine, to block the behavioural effects of phencyclidine in mice was investigated. N(omega)-propyl-L-arginine (20 mg/kg) was found to block both phencyclidine (4 mg/kg)-induced disruption of prepulse inhibition and phencyclidine-induced stimulation of locomotor activity in the mice tested. It is concluded that the NOS-sensitive behavioural effects of phencyclidine in rodents is dependent on neuronal NOS and that NO may play a role in the psychotomimetic effects of phencyclidine.
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PMID:The neuronal selective nitric oxide synthase inhibitor, Nomega-propyl-L-arginine, blocks the effects of phencyclidine on prepulse inhibition and locomotor activity in mice. 1549 4

Nitric oxide (NO) is a diffusible, multifunctional signaling molecule found in many areas of the brain. NO signaling is involved in a wide array of neurophysiological functions including synaptogenesis, modulation of neurotransmitter release, synaptic plasticity, central nervous system blood flow and cell death. NO synthase (NOS) activity regulates the production of NO and the cerebellum expresses high levels of nitric oxide synthase (NOS) in granule, stellate and basket cells. Cerebellar mutant mice provide excellent opportunities to study changes of NO/NOS concentrations and activities to gain a greater understanding of the roles of NO and NOS in cerebellar function. Here, we have reviewed the current understanding of the functional roles of NO and NOS in the cerebellum and present NO/NOS activities that have been described in various cerebellar mutant mice and NOS knockout mice. NO appears to exert neuroprotective effects at low to moderate concentrations, whereas NO becomes neurotoxic as the concentration increases. Excessive NO production can cause oxidative stress to neurons, ultimately impairing neuronal function and result in neuronal cell death. Based on their genetics and cerebellar histopathology, some of cerebellar mutant mice display similarities with human neurological conditions and may prove to be valuable models to study several human neurological disorders, such as autism and schizophrenia.
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PMID:Neuronal nitric oxide synthase expression in cerebellar mutant mice. 1554 2

The psychotomimetic drugs, phencyclidine (PCP) and MK-801, are non-competitive antagonists of the N-methyl-d-aspartate (NMDA) receptor and used as pharmacological tools to mimic a possible NMDA receptor hypofunction in schizophrenia. These drugs were tested in two behavioural paradigms in the present study: prepulse inhibition (PPI) of acoustic startle and locomotor activity (LMA) in an open field. Recent studies show that several behavioural and biochemical effects of PCP are blocked by nitric oxide synthase (NOS) inhibition. Hence, it is likely that some effects of PCP are mediated via an increase in NO production, an assumption not in accordance with the NMDA receptor antagonistic effect of PCP. Experiments were conducted in rats to further elucidate the involvement of NO-dependent mechanisms in the effects of PCP and MK-801, and how these effects may involve the NMDA receptor. The NOS inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) (10 mg/kg) normalised the disruptive effect of PCP (2 mg/kg) on PPI and the stimulatory effect of PCP (4 mg/kg) on LMA. In contrast to these observations, the deficit in PPI induced by MK-801 (0.1 mg/kg) was not affected by L-NAME (10, 20 or 40 mg/kg). MK-801 (0.15 mg/kg)-induced hyperlocomotion was not affected by L-NAME (10 mg/kg), but attenuated by L-NAME (40 mg/kg). Furthermore, receptor binding studies aimed at investigating the influence of L-NAME on the binding of PCP to the MK-801-sensitive NMDA receptor binding site failed to show such an influence. These results suggest that the NO-sensitive effects of PCP are not sufficiently explained by its antagonistic effect at the NMDA receptor channel complex.
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PMID:Selective interaction of nitric oxide synthase inhibition with phencyclidine: behavioural and NMDA receptor binding studies in the rat. 1579 2

Alterations in antioxidant status in schizophrenia suggest free radical-mediated neurotoxicity; this finding can be a consequence of increased free radical production. There are multiple pathways to excess free radical generation and subsequent oxidative stress. One such pathway is the formation of peroxynitrite by a reaction of nitric oxide (NO) and superoxide radical. NO is formed from L-arginine by nitric oxide synthase (NOS). A constitutive cytosolic isoform, neuronal NOS (nNOS), appears to be fairly stable in the postmortem brain tissues. Utilizing a sensitive fluorometric assay, NO levels were measured by its stable metabolites, nitrate and nitrite, in the caudate region of postmortem brain tissues from patients and control subjects. In the human brain, NO is metabolized primarily in the form of nitrate. A significantly increased level of NO was found in schizophrenia patients (241 +/- 146 pmol/mg dry weight, n = 18) than was found in those of normal (142 +/- 65 pmol/mg dry weight, n = 20) and psychiatric controls without schizophrenia (125 +/- 83 pmol/mg dry weight, n = 16) (analysis of covariance [ANCOVA], F = 6.446, df = 2,51, p = 0.003). These findings were independent of age, brain weight, postmortem interval (PMI), sample storage time, or cigarette smoking. Elevated NO levels in the brains of schizophrenia patients lend further support for the free radical pathology in schizophrenia.
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PMID:Increased nitric oxide radicals in postmortem brain from patients with schizophrenia. 1595 98

Prepulse inhibition of acoustic startle is a behavioural response, which is used to estimate sensorimotor gating deficits in schizophrenia. Recent studies show that several behavioural effects of the psychotomimetic drug, phencyclidine (PCP), in rodents are blocked by nitric oxide synthase (NOS) inhibitors suggesting that NO plays an important role in the pharmacological effects of PCP. The present study was conducted to examine the effects of PCP on prepulse inhibition in neuronal NOS (nNOS) deficient mice. PCP treatment caused a significant and dose-related increase in prepulse inhibition in nNOS-/- mice whereas prepulse inhibition was not significantly affected in +/+ and +/- mice. Basal prepulse inhibition level did not differ significantly between the groups. Furthermore, PCP caused a dose-related decrease in startle response reactivity in +/+ mice but did not significantly affect this measure in +/- and -/- mice. Basal startle response level did not differ between +/+ and +/- but was significantly lower in -/- mice. It is concluded that nNOS plays a role in the NO-sensitive effects of PCP.
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PMID:Effects of phencyclidine on acoustic startle and prepulse inhibition in neuronal nitric oxide synthase deficient mice. 1613 76

Depression is frequently associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to repeated episodes of hypercortisolemia. Hypothalamic paraventricular neurons are believed to trigger these processes by aberrant generation and/or release of corticotropin releasing hormone, oxytocin, vasopressin, and nitric oxide (NO). Recent findings from two independent laboratories have demonstrated that the suprachiasmatic nucleus, which in part controls the cellular activity of paraventricular neurons (PVN), is also involved in affective disorder. The aim of the present study was to elucidate by stereological analysis, whether suprachiasmatic nucleus (SCN) nitric oxide synthase and neurophysin generating neurons are affected in neuropsychiatric disorders. We show that compared to controls the number of nitric oxide synthase immunoreactive neurons is greatly reduced both in depression and in schizophrenia. In subjects with affective disorder there was a correlation between the number of NOS-expressing cells and duration of treatment with antidepressants. The number of neurophysin-expressing SCN neurons was also fewer in cases with mood disorder. It is concluded that SCN-derived NO may be a relevant pathophysiological factor in neuropsychiatric disorders.
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PMID:Hypothalamic nitric oxide synthase in affective disorder: focus on the suprachiasmatic nucleus. 1619 95

Tetrahydrobiopterin (BH(4)) is a vital cofactor maintaining availability of the amine neurotransmitters [dopamine (DA), noradrenaline (NA), and serotonin (5-HT)], regulating the synthesis of nitric oxide (NO) by nitric oxide synthase (NOS), and stimulating and modulating the glutamatergic system (directly and indirectly). These BH(4) properties and their potential relevance to schizophrenia led us to investigate the hypothesis of a study group (healthy controls, n=37; schizophrenics, n=154) effect on fasting plasma total biopterin levels (a measure of BH(4)). Study analysis showed a highly significant deficit of total biopterins for the schizophrenic sample after partialling out the effects of potential confounds of gender, age, ethnicity, neuroleptic use history and dose of current use, 24-hour dietary phenylalanine/protein ratio (a dietary variable relevant to BH(4) synthesis), and plasma phenylalanine (which stimulates BH(4) synthesis). A mean decrement of 34% in plasma total biopterins for schizophrenics from control values supports clinical relevance for the finding. In a subsample (21 controls and 23 schizophrenics), sequence analysis was done of the GTP cyclohydrolase I feedback regulatory gene and no mutations were found in the coding region of the gene. A deficiency of BH(4) could lead to hypofunction of the systems of DA, NA, 5-HT, NOS/NO, and glutamate, all of which have been independently implicated in schizophrenia psychopathology. Further, evidence has been accumulating which implicates the critical interdependence of these neurotransmitter systems in schizophrenia; this concept, along with the present study finding of a biopterin deficit, suggests that further study of the BH(4) system in schizophrenia is warranted and desirable.
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PMID:Evidence for a tetrahydrobiopterin deficit in schizophrenia. 1624

Cognitive deficits of schizophrenia constitute a disabling part of the disease predicting treatment success as well as functional outcome. Phencyclidine (PCP), a non-competitive NMDA receptor antagonist was used to model schizophrenic cognitive dysfunctions of learning and memory using the Morris water maze paradigm for reference memory. In experiment 1 male Sprauge-Dawley rats were acutely administered PCP (0.5, 1.0 and 2.0 mg/kg s.c.) before the first swim session on each of the four acquisition days. Probe test for reference memory was performed 2 days after the last acquisition day; the first probe without drug treatment to assess reference memory and a second probe with prior drug treatment to control for state dependency effects of PCP. In experiment 2 the effects of pre-treatment (10 min before PCP) with the nitric oxide synthase inhibitor, L-NAME (10 mg/kg s.c.), on the PCP (2 mg/kg)-induced spatial memory deficit was evaluated in the Morris water maze paradigm for reference memory. The results showed that PCP in a dose of 2 mg/kg disrupts spatial learning as estimated by prolonged search time to find platform during acquisition as well as the reference memory test as measured by less time spent in target quadrant during probe trial. No state dependency effects of PCP were found. Pre-treatment with L-NAME completely reversed the PCP-induced disruption of acquisition learning. The reference memory disruption was, however, not completely restored as measured by probe trial.
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PMID:Effects of phencyclidine on spatial learning and memory: nitric oxide-dependent mechanisms. 1667 24

Phencyclidine (PCP), a non-competitive NMDA receptor antagonist, was used to model schizophrenia-like cognitive dysfunctions of learning and memory in rats using the Morris water maze model for spatial memory. A protocol introduced by Baldi and co-workers was used to distinguish working memory from reference memory. Male Sprague-Dawley rats were administered PCP (2.0 mg/kg) before the first swimming trial on each of five spatial memory acquisition days, either alone or after pre-treatment with the nitric oxide synthase inhibitor, L-NAME (10 mg/kg). Probe tests for memory were conducted before and after each acquisition session. The results showed that PCP disrupted the acquisition of both working and reference memory. Pre-treatment with L-NAME reversed both these effects of PCP. L-NAME treatment by itself did not significantly alter either acquisition or retention of spatial memory.
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PMID:Phencyclidine affects memory in a nitric oxide-dependent manner: working and reference memory. 1693 57

The gaseous messenger NO has repeatedly been suggested to play a role in the pathogenesis of psychoses. Following a pilot study, we investigated whether the number of nitrinergic neurons in the putamen of patients suffering from schizophrenia, bipolar disorder or major depression is altered. Post-mortem striatum sections of 15 brains from patients with either disease were examined by NADPH-diaphorase staining, which selectively labels NO synthase-positive interneurons. Quantification of these cells revealed significantly lower numbers of NO synthase-containing neurons in the putamen of schizophrenic patients. Our results suggest that striatal nitrinergic interneurons are involved in the pathophysiology of at least some forms of schizophrenia, such as e.g. catatonic schizophrenia.
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PMID:NO synthase-positive striatal interneurons are decreased in schizophrenia. 1726 81


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