Statistical Parametric Mapping reveals ligand and region-specific activation of G-proteins by CB1 receptors and non-CB1 sites in the 3D reconstructed mouse brain.
Statistical Parametric Mapping reveals ligand and region-specific activation of G-proteins by CB1 receptors and non-CB1 sites in the 3D reconstructed mouse brain.
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DOI：
10.1016/j.neuroimage.2010.04.259
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发表时间：
2010-10-01
期刊：
影响因子：
5.7
通讯作者：
Sim-Selley, L. J.
中科院分区：
文献类型：
--
作者：
Nguyen, P. T.;Selley, D. E.;Sim-Selley, L. J.
Cb1受体介导Δ、9-四氢大麻酚和合成大麻素的中枢神经系统效应。以前的研究已经研究了大麻素介导的G蛋白在被认为介导大麻素行为影响的脑区的子集中的活性，但还没有对多个配体的影响进行详细的区域比较。本研究使用一种新的方法-统计参数映射(SPM)，以全脑无偏的方式分析激动剂刺激的[35S]GTPγS放射自显影重建的脑图像。SPM分析表明，大麻素激动剂甲烷胺(M-AEA)、CP55,940(CP)和WIN55,212-2(WIN)在CB1+/+小鼠脑中的相对有效性存在地区差异。为了评估新的大麻素结合位点的潜在贡献，我们在CB1−/−小鼠的大脑中进行了实验。扫描电子显微镜分析表明，氨基烷基吲哚可刺激大脑皮层、海马、下丘脑、杏仁核、小脑和某些脑干区(背被盖复合体和蓝斑)的[35S]GTPγ与S结合，而双环大麻素CP和内源性大麻类似物M-AEA则无此作用。在基底节，Win刺激的G蛋白活性与基础活性没有差异。使用CB1拮抗剂SR141716A对CB1+/+小鼠进行的药理实验表明，SR141716A阻断了Win刺激的所有脑区的G蛋白活性，表明它既能与CB1结合，也能与推测的非CB1位点结合。这些研究显示了配基和区域特异性大麻素介导的G蛋白在CB1和非CB1位点的活性，并表明SPM是分析激动剂刺激的[35S]GTPγS放射自显影重建脑成像数据的有效方法。
CB1 receptors mediate the CNS effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids. Previous studies have investigated cannabinoid-mediated G-protein activity in a subset of brain regions thought to mediate the behavioral effects of cannabinoids, but a detailed regional comparison of the effects of multiple ligands has not been conducted. This study used a novel approach, Statistical Parametric Mapping (SPM), to analyze 3D reconstructed brain images derived from agonist-stimulated [35S]GTPγS autoradiography in a whole-brain unbiased manner. SPM analysis demonstrated regional differences in the relative efficacies of cannabinoid agonists methanandamide (M-AEA), CP55,940 (CP) and WIN55,212-2 (WIN) in CB1+/+ mouse brains. To assess the potential contribution of novel cannabinoid binding sites, experiments were performed in CB1−/− mouse brains. SPM analysis revealed that the aminoalkylindole WIN, but not the bicyclic cannabinoid CP or the endocannabinoid analogue M-AEA, stimulated [35S]GTPγS binding in cortex, hippocampus, hypothalamus, amygdala, cerebellum and certain brainstem areas (dorsal tegmental complex and locus coeruleus). No differences between WIN-stimulated G-protein activity and basal activity were found in basal ganglia. Pharmacological experiments using the CB1 antagonist SR141716A in CB1+/+ mice showed that SR141716A blocked WIN-stimulated G-protein activity in all brain regions, suggesting that it binds to both CB1 and putative non-CB1 sites. These studies show ligand and region specific cannabinoid-mediated G-protein activity at both CB1 and non-CB1 sites and demonstrate that SPM is a powerful approach for the analysis of reconstructed brain imaging data derived from agonist-stimulated [35S]GTPγS autoradiography.
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