Boileau Isabelle, Guttman Mark, Rusjan Pablo, Adams John R, Houle Sylvain, Tong Junchao, Hornykiewicz Oleh, Furukawa Yoshiaki, Wilson Alan A, Kapur Shitij, Kish Stephen J
Human Neurochemical Pathology Laboratory, University of Toronto, Toronto, Ontario, Canada.
Brain. 2009 May;132(Pt 5):1366-75. doi: 10.1093/brain/awn337. Epub 2009 Jan 19.
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.
D(3)多巴胺（DA）受体是D(2)样DA受体家族的成员。虽然D(2)受体在纹状体的运动区域尤其丰富，但D(3)受体在边缘区域和苍白球中相对丰富。由于该受体可能与帕金森病的精神和运动并发症有关，且多巴胺D(3)偏好激动剂疗法可能延缓疾病进展，因此目前在神经病学领域备受关注。临床前数据表明，黑质纹状体DA神经元损伤后，D(3)（而非D(2)）DA受体的纹状体水平降低；目前，尚无关于帕金森病中该受体亚型的体内数据。本正电子发射断层扫描研究的目的是比较[(11)C]-(+)-PHNO（D(3)与D(2)偏好）和[(11)C]雷氯必利（D(3)=D(2)）在未患抑郁症、未患痴呆症、未使用多巴胺能药物的早期帕金森病患者（n = 10）大脑中的结合情况，并与匹配的对照组（n = 9）进行比较。帕金森病与富含D(3)的腹侧纹状体中[(11)C]-(+)-PHNO（而非[(11)C]雷氯必利）结合呈双侧下降趋势（-11%，P = 0.07）以及苍白球中结合显著下降（-42%，P = 0.02）有关。相比之下，在主要为D(2)分布的壳核中，[(11)C]-(+)-PHNO（25%，P = 0.02）和[(11)C]雷氯必利（25%，P < 0.01）的结合均同样增加，尤其是在症状对侧。在中脑，推测含有定位于黑质的D(3)受体，[(11)C]-(+)-PHNO结合正常。[(11)C]-(+)-PHNO与[(11)C]雷氯必利的结合比值降低与运动功能障碍和情绪低落相关（P < 0.02）。我们的成像数据表明，人类大脑中DA神经元的丧失会导致DA D(2)和D(3)受体出现区域特异性的差异变化，D(3)受体的“下调”可能与帕金森病的一些运动和情绪问题有关。D(3)受体水平可能是治疗相关副作用的一个决定性易损因素；因此，这些初步发现为理解D(3)受体在帕金森病药物反应中的作用提供了有价值的基线信息。
