Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naive Parkinson's disease.
The D(3) dopamine (DA) receptor is a member of the D(2)-like DA receptor family. While the D(2) receptor is abundant especially in motor-regions of the striatum, the D(3) 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 D(3)-preferring agonist therapy might delay progression of the disorder. Preclinical data indicate that striatal levels of the D(3) (but not the D(2)) 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 [(11)C]-(+)-PHNO (D(3) versus D(2) preferring) and [(11)C]raclopride (D(3) = D(2)) 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 [(11)C]-(+)-PHNO (but not [(11)C]raclopride) binding in the D(3)-rich ventral striatum (-11%, P = 0.07) and significantly decreased binding in globus pallidus (-42%, P = 0.02). In contrast, in the primarily D(2)-populated putamen, both [(11)C]-(+)-PHNO (25%, P = 0.02) and [(11)C]raclopride (25%, P < 0.01) binding were similarly increased, especially on the side contra-lateral to the symptoms. In the midbrain, presumably containing D(3) receptors localized to the substantia nigra, [(11)C]-(+)-PHNO binding was normal. Decreased [(11)C]-(+)-PHNO to [(11)C]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 D(2) and D(3) receptors with D(3) receptor 'downregulation' possibly related to some motor and mood problems in Parkinson disease. D(3) 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 D(3) receptors in response to Parkinson's disease medication.
Boileau
Isabelle
I
Human Neurochemical Pathology Laboratory, University of Toronto, Toronto, Ontario, Canada. isabelle_boileau@CAMH.net
Guttman
Mark
M
Rusjan
Pablo
P
Adams
John R
JR
Houle
Sylvain
S
Tong
Junchao
J
Hornykiewicz
Oleh
O
Furukawa
Yoshiaki
Y
Wilson
Alan A
AA
Kapur
Shitij
S
Kish
Stephen J
SJ
D000368:Aged; D001667:Binding, Competitive; D002250:Carbon Radioisotopes / Q000378:metabolism; D016022:Case-Control Studies; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D005917:Globus Pallidus / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines / Q000378:metabolism*; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D049268:Positron-Emission Tomography; D020891:Raclopride / Q000378:metabolism / Q000627:therapeutic use; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D018709:Statistics, Nonparametric
D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D010078:Oxazines; D050637:Receptors, Dopamine D3; C042631:naxagolide; D020891:Raclopride; D004298:Dopamine