Department of Translational Neuroscience and Molecular Imaging Center, University of Antwerp, Antwerp, Belgium.
J Pharmacol Exp Ther. 2011 Oct;339(1):210-7. doi: 10.1124/jpet.111.182766. Epub 2011 Jul 8.
Phosphodiesterase 10A (PDE10A) inhibitors have recently been proposed as a new therapy for schizophrenia. The aim of this study was to enhance our understanding of the role of PDE10A inhibitors and potentially identify a clinically useful mechanistic/functional biomarker by using 2-deoxyglucose (2-DG) autoradiography. PDE10A inhibitors papaverine (10 and 40 mg/kg), 6,7-dimethoxy-4-[(3R)-3-(2-quinoxalinyloxy)-1-pyrrolidinyl]quinazoline (PQ-10), (0.16-10 mg/kg), and 2-[{4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy}methyl]quinoline (MP-10) (0.16-40 mg/kg) induced region-specific hypermetabolism in the globus pallidus and lateral habenula of C57BL/6 mice. Studies with MP-10 revealed a dose-dependent relative increase in globus pallidus activation, whereas a bell-shaped curve was observed for the lateral habenula. Although the relative increase in 2-DG uptake in the lateral habenula was also characteristic of the D(2) antagonist haloperidol (0.01-0.63 mg/kg), relative 2-DG changes were absent in the globus pallidus. This observation probably is explained by the interaction of PDE10A inhibitors with the D(1) direct pathway as suggested by experiments in combination with the D(1) agonist (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-82958) (0.16 mg/kg). The absence of an effect of MP-10 (2.5 mg/kg) on relative glucose metabolism in the globus pallidus and lateral habenula of PDE10A knockout mice confirmed the specificity of the signal induced by PDE10A inhibitors. These studies substantiate the regulatory role of PDE10A in the basal ganglia circuit and as such support the potential of PDE10A inhibitors for treating psychiatric disorders. Moreover, we could differentiate PDE10A inhibitors from haloperidol based on specific patterns of hypermetabolism probably caused by its combined action at both direct and indirect dopaminergic pathways. Finally, these specific changes in brain glucose metabolism may act as a translational biomarker for target engagement in future clinical studies.
磷酸二酯酶 10A（PDE10A）抑制剂最近被提议作为精神分裂症的一种新疗法。本研究旨在通过使用 2-脱氧葡萄糖（2-DG）放射自显影术，增强我们对 PDE10A 抑制剂作用的理解，并可能确定一种具有临床应用价值的机制/功能生物标志物。PDE10A 抑制剂罂粟碱（10 和 40mg/kg）、6,7-二甲氧基-4-[(3R)-3-(2-喹喔啉基氧基)-1-吡咯烷基]喹唑啉（PQ-10）（0.16-10mg/kg）和 2-[[4-(1-甲基-4-吡啶-4-基-1H-吡唑-3-基)苯氧基]甲基]喹啉（MP-10）（0.16-40mg/kg）在 C57BL/6 小鼠的苍白球和外侧缰核中诱导区域特异性代谢亢进。用 MP-10 进行的研究表明，苍白球激活呈剂量依赖性相对增加，而外侧缰核则呈现钟形曲线。尽管外侧缰核中 2-DG 摄取的相对增加也与 D2 拮抗剂氟哌啶醇（0.01-0.63mg/kg）特征一致，但苍白球中没有相对 2-DG 变化。这种观察结果可能是由于 PDE10A 抑制剂与 D1 直接途径相互作用所致，如与 D1 激动剂（±）-6-氯-7,8-二羟基-3-丙烯基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓氢溴酸盐（SKF-82958）（0.16mg/kg）联合进行的实验所表明的那样。在 PDE10A 基因敲除小鼠的苍白球和外侧缰核中，MP-10（2.5mg/kg）对相对葡萄糖代谢无影响，证实了 PDE10A 抑制剂诱导的信号的特异性。这些研究证实了 PDE10A 在基底节回路中的调节作用，从而支持 PDE10A 抑制剂治疗精神疾病的潜力。此外，我们可以根据其在直接和间接多巴胺能途径中的联合作用引起的特定代谢亢进模式，将 PDE10A 抑制剂与氟哌啶醇区分开来。最后，这些大脑葡萄糖代谢的特定变化可能作为未来临床研究中靶标结合的转化生物标志物。
