Regulation of dopaminergic function: an [18F]-DOPA PET apomorphine challenge study in humans.
Dopaminergic function has a key role in normal brain function, dopaminergic dysfunction being implicated in numerous neuropsychiatric disorders. Animal studies show that dopaminergic stimulation regulates dopaminergic function, but it is not known whether this exists in humans. In the first study (study 1), we measured dopamine synthesis capacity (indexed as Kicer) to identify the relationship between baseline and change in Kicerunder resting conditions for comparison with effects of dopaminergic stimulation. In the second study (study 2), we used a within-subjects design to test effects of dopaminergic stimulation on dopamine synthesis capacity. In study 1, eight volunteers received two18F-DOPA scans on separate days, both at rest. In study 2, 12 healthy male volunteers received two18F-DOPA positron emission tomographic (PET) scans after treatment with either the dopamine partial agonist apomorphine (0.03 or 0.005 mg kg-1) or placebo. In study 1, no significant correlation was found between baseline and change in dopamine synthesis capacity between scans (r=-0.57, n=8, P=0.17, two-tailed). In study 2, a significant negative correlation was found between baseline dopamine synthesis capacity and percentage change in dopamine synthesis capacity after apomorphine challenge (r=-0.71, n=12, P=0.01, two-tailed). This correlation was significantly different (P<0.01) from the correlation between baseline and change in dopamine synthesis capacity under unstimulated conditions. One-way repeated-measures analysis of variance showed a significant group (study 1/study 2) × time interaction (F(1,18)=11.5, P=0.003). Our findings suggest that regulation of dopamine synthesis capacity by apomorphine depends on baseline dopamine function, consistent with dopamine stimulation stabilizing dopaminergic function. Loss of this autoregulation may contribute to dopaminergic dysfunction in brain disorders such as schizophrenia, substance dependence, and Parkinson's disease.
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
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Jauhar
Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
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Veronese
MRC London Institute of Medical Sciences, London, UK.
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Rogdaki
MRC London Institute of Medical Sciences, London, UK.
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Bloomfield
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
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Natesan
Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
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Turkheimer
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
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Kapur
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.|MRC London Institute of Medical Sciences, London, UK.|Institute of Clinical Sciences, Department of Medicine, Imperial College London, London, UK.
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Howes
D000328:Adult; D001058:Apomorphine / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D055815:Young Adult
D018491:Dopamine Agonists; D019275:Radiopharmaceuticals; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D001058:Apomorphine; D004298:Dopamine