Brain Advance Access originally published online on January 19, 2009
Brain 2009 132(5):1366-1375; doi:10.1093/brain/awn337
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Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naïve Parkinson's disease
1 Human Neurochemical Pathology Laboratory, University of Toronto, Toronto, Ontario, Canada 2 Centre for Movement Disorders, Markham, Ontario, Canada 3 Vivian M. Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada 4 Center for Brain Research, Medical University of Vienna, Vienna, Austria
Correspondence to: Isabelle Boileau, PhD, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8 E-mail: isabelle_boileau{at}CAMH.net
The D3 dopamine (DA) receptor is a member of the D2-like DA receptor family. While the D2 receptor is abundant especially in motor-regions of the striatum, the D3 receptor shows a relative abundance in limbic regions and globus pallidus. This receptor is of current interest in neurology because of its potential involvement in psychiatric and motor complications in Parkinson's disease and the possibility that dopamine D3-preferring agonist therapy might delay progression of the disorder. Preclinical data indicate that striatal levels of the D3 (but not the D2) DA receptor are decreased following lesion of nigrostriatal DA neurons; at present, there are no in vivo data on this receptor subtype in Parkinson's disease. The objective of this positron emission tomography study was to compare [11C]-(+)-PHNO (D3 versus D2 preferring) and [11C]raclopride (D3 = D2) binding in brain of non-depressed, non-demented, dopaminergic drug-naïve patients with early-stage Parkinson's disease (n = 10), relative to matched-controls (n = 9). Parkinson's disease was associated with a trend for bilaterally decreased [11C]-(+)-PHNO (but not [11C]raclopride) binding in the D3-rich ventral striatum (–11%, P = 0.07) and significantly decreased binding in globus pallidus (–42%, P = 0.02). In contrast, in the primarily D2-populated putamen, both [11C]-(+)-PHNO (25%, P = 0.02) and [11C]raclopride (25%, P < 0.01) binding were similarly increased, especially on the side contra-lateral to the symptoms. In the midbrain, presumably containing D3 receptors localized to the substantia nigra, [11C]-(+)-PHNO binding was normal. Decreased [11C]-(+)-PHNO to [11C]raclopride ratio correlated with motor deficits and lowered-mood (P < 0.02). Our imaging data suggest that brain DA neuron loss in the human causes region-specific differential changes in DA D2 and D3 receptors with D3 receptor ‘downregulation’ possibly related to some motor and mood problems in Parkinson disease. D3 receptor levels might be a determinant vulnerability factor underlying side-effects associated with treatment; hence, these initial findings provide valuable baseline information to understand the role of D3 receptors in response to Parkinson's disease medication.
Key Words: [11C]raclopride; [11C]-(+)-PHNO; Dopamine D2/3 receptors; Parkinson's disease; positron emission tomography (PET)
Abbreviations: DA, dopamine; DC, dorsal caudate; DP, dorsal putamen; GP, globus pallidus; PET, positron emission tomography; ROI, region of interest; VS, ventral striatum
Received September 22, 2008. Revised November 10, 2008. Accepted November 13, 2008.