Thesis

An investigation of nitric oxide synthase in neuronal function and in phencyclidine models of relevance to schizophrenia

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Awarding institution
  • University of Strathclyde
Date of award
  • 2014
Thesis identifier
  • T13724
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Abstract
  • Schizophrenia is a complex and debilitating psychiatric disorder. Dysfunction of the NMDA subtype of glutamate receptors is implicated in deficits found in schizophrenia, and some of these deficits may be reproduced in rodents using the NMDA receptor antagonist, phencyclidine (PCP). Nitric oxide synthase (NOS) is the synthesising enzyme of the gaseous neuromodulator, nitric oxide. The neuronal isoform of NOS (nNOS) is functionally associated with NMDA receptors. The role of NOS in schizophrenia is not fully understood. The primary aim of this thesis is to investigate NOS signalling in cultured neurones and in rodent PCP models of relevance to schizophrenia. Using diaminofluorescein microscopy of primary neuronal cultures, it is shown that non-selective inhibition of NOS using L-NAME, and selective inhibition of nNOS using L-NPA reversed glutamate-stimulated nitric oxide generation in hippocampal and cerebellar neurones, but inhibition of endothelial NOS using L-NIO did not. Novel compounds that modulate the NOS cofactor, tetrahydrobiopterin, altered nitric oxide generation in cerebellar neurones. NOS activity was increased in the hippocampus, and decreased in the reticular thalamus in mice administered acute PCP (5 mg.kg-1, i.p.), as determined by NADPH-diaphorase activity. NOS activity normalised in these areas with subchronic PCP (5 mg.kg-1 twice daily for 5 days), and NOS activity was decreased in the prefrontal cortex. Decreased activity of thioredoxin reductase was found in the hippocampus and thalamus with acute PCP, but was unchanged with subchronic PCP. Pretreatment with L-NAME (40 mg.kg-1) and L-NIO (20 mg.kg-1) improved hyperlocomotion and III deficits in prepulse inhibition observed with PCP, but L-NPA (20 mg.kg-1) did not. In conclusion, the results presented in this thesis give evidence for a role of NOS in deficits observed in rodent PCP models of relevance to schizophrenia. Selective inhibition of NOS isoforms is a potential therapeutic strategy to improve deficits associated with NMDA receptor dysfunction found in schizophrenia.
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DOI
Date Created
  • 2014
Former identifier
  • 1032422

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