Decreased binding of the D3 dopamine receptor-preferring ligand [C]-(+)-PHNO in drug-naı̈ve Parkinson’s disease

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 [C]-(+)-PHNO (D3 versus D2 preferring) and [ C]raclopride (D3 =D2) binding in brain of non-depressed, non-demented, dopaminergic drug-naı̈ve 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 [C]-(+)-PHNO (but not [C]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 [C]-(+)-PHNO (25%, P=0.02) and [C]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, [ C]-(+)-PHNO binding was normal. Decreased [C]-(+)-PHNO to [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 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.