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Title: Molecular imaging of dopamine synthesis and release
Author: Shotbolt, John
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Positron emission tomography (PET) can be used to measure striatal dopamine synthesis and release, both of which have been shown to be elevated in schizophrenia. One study has demonstrated that first degree relatives of schizophrenia patients exhibit increased dopamine synthesis capacity, suggesting this could be an endophenotype or susceptibility marker. However, the specific relation to schizophrenia was not tested, as the index cases were not studied. In this thesis, I directly tested the hypothesis that both members of twin pairs discordant for schizophrenia show similar increases in dopamine synthesis capacity. I found that striatal dopamine synthesis capacity is not elevated in individuals at genetic risk of schizophrenia or in stable patients with chronic schizophrenia, suggesting that it is not a vulnerability marker for schizophrenia, and is associated with active psychosis only. I also tested whether dopamine synthesis capacity is elevated in otherwise healthy people who report hallucinations. No elevation was found, suggesting that the underlying neurobiology is distinct from schizophrenia. I then considered whether it would be possible to examine similar relationships with measurements of dopamine release. Methodologies for this measurement were still limited: antagonist radioligands such as [11C] raclopride have been used, but the dynamic range for the measure is small, confounding precision. I hypothesised that agonist radioligands could provide a more sensitive measure. [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ([11C]-(+)-PHNO) is a D2/D3 agonist PET radioligand. I directly compared the sensitivity of [11C]-(+)-PHNO to amphetamine challenge with that of the antagonist ligand [11C] raclopride. Mass carry-over and cerebellar binding were potential problems with [11C]-(+)-PHNO. I therefore designed a study to quantify these factors. I found that [11C]-(+)-PHNO is superior to [11C]raclopride for studying acute fluctuations in dopamine in the striatum. Use of [11C]-(+)-PHNO will allow quantification of smaller changes in dopamine release, although mass effects and displaceable cerebellar binding are potential confounding factors.
Supervisor: Matthews, Paul ; Rabiner, Eugenii Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available