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Title: In vivo categorisation of ketamine's effects on the rat brain : relevance for schizophrenia
Author: Blockeel, Anthony James
ISNI:       0000 0004 2725 1678
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2011
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Acute administration of ketamine in human subjects transiently induces a state reminiscent of schizophrenia. Shared symptoms include psychosis, thought disorder and working memory impairments. The administration ofNMDA receptor (NMDAR) antagonists like ketamine has therefore become a widely utilised model of schizophrenia in humans, non-human primates and rodents. Whilst NMDARs are the predominant site of ketamine's direct action, NMDAR antagonism is likely to trigger a cascade of downstream effects that together contribute to the psychotomimetic state. This thesis aims to identify how these changes impact normal function of the brain at a range of levels from the single cell to global metabolism. Pharmacokinetic studies determined a dose of ketamine in rats resulting in plasma concentrations comparable to those used in the human studies. Semi-quantitative 2- deoxyglucose (2-DG) autoradiography identified brain regions whose metabolism was modulated by ketamine, including several implicated in the pathophysiology of schizophrenia: 2-DG uptake increased in subdivisions of frontal cortex and decreased in hippocampus, auditory cortex and medial septum. Given these divergent 2-DG effects in medial prefrontal cortex (mPFC) and hippocampus, simultaneous electrophysiological recordings were performed in these two areas to detail ketamine's effects in behaving rats. At the neural network level, ketamine induced aberrant and sustained gamma oscillations in both structures, but decreased theta oscillations in hippocampus whilst inducing high-frequency oscillations in mPFC. Average firing rates of single neurons were not sensitive to ketamine, but patterns of mPFC pyramidal cell firing were profoundly disrupted in line with aberrant gamma rhythms. Ketamine was also found to modulate components of cortical and hippocampal auditory evoked potentials, indicating that it can cause deficits in basic sensory processing. Finally, in line with similar deficits in schizophrenia, a pilot study investigated ketamine's ability to impair higher-level cognition in rats by assaying performance on an attentional set-shifting task. In summary, ketamine administration can mimic a subset of schizophrenia's symptomatology in rats. Consequently the ketamine model of schizophrenia remains pertinent to schizophrenia research, but only as part of a broader strategy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available