Division of Nuclear Medicine, University Hospitals Leuven, KU Leuven, 3000, Leuven, Belgium,
Eur J Nucl Med Mol Imaging. 2013 Oct;40(10):1582-94. doi: 10.1007/s00259-013-2456-1. Epub 2013 Jun 6.
Recent biochemical and post-mortem evidence suggests involvement of the endocannabinoid system in alcohol drinking behaviour and dependence. Using [(18)F]MK-9470 small-animal PET imaging, our primary objective was to evaluate in vivo type 1 cannabinoid receptor (CB1R) binding changes in rats subjected to several ethanol conditions: (1) at baseline, (2) after acute intraperitoneal administration of ethanol (4 g/kg) or saline, (3) after 7 days of forced chronic ethanol consumption, and (4) after abstinence for 7 and 14 days. Secondly, levels of anandamide (AEA) in the nucleus accumbens (NAcc) were investigated in the same animals using in vivo microdialysis and correlated with the changes in CB1R binding.
In total, 28 male Wistar rats were investigated. Small-animal PET was done on a FOCUS-220 tomograph with [(18)F]MK-9470. Parametric images of [(18)F]MK-9470 binding based on standard uptake values (SUV, as a measure of CB1R binding) were generated. Images were normalized to Paxinos space and analysed voxel-wise using SPM8 (p(height) = 0.005; k(ext) = 200). The AEA content was quantified using HPLC with tandem mass spectrometry detection.
Acute ethanol administration increased relative CB1R binding in the NAcc that was positively correlated with the change in AEA levels of that region. In contrast, compared to rats at baseline, AEA levels in the NAcc were not significantly different in rats after chronic ethanol consumption or after a 14-day abstinence period. Chronic ethanol consumption decreased relative CB1R binding in the hippocampus and caudate-putamen, whereas same regions showed increased relative CB1R binding after 7 and 14 days of abstinence compared to the baseline condition. After 7 and 14 days of abstinence, relative CB1R binding additionally decreased in the orbitofrontal cortex. The magnitude of the hippocampal and frontal changes was highly correlated with daily ethanol intake.
This study provides in vivo evidence that acute ethanol consumption is associated with enhanced endocannabinoid signalling in the NAcc, indicated by an increased CB1R binding and AEA content. In addition, chronic ethanol exposure leads to regional dysfunctions in CB1R levels, involving the hippocampus and caudate-putamen that are reversible within 2 weeks in this animal model.
最近的生化和尸检证据表明，内源性大麻素系统参与了饮酒行为和依赖。本研究使用 [(18)F]MK-9470 小动物 PET 成像，主要目的是评估几种乙醇条件下大鼠体内 1 型大麻素受体 (CB1R) 结合的变化：(1) 基线时，(2) 急性腹腔内给予乙醇 (4 g/kg) 或生理盐水后，(3) 强制慢性乙醇消耗 7 天后，(4) 禁欲 7 和 14 天后。其次，使用同一动物的活体微透析法研究了伏隔核 (NAcc) 中的花生四烯酸酰胺 (AEA) 水平，并将其与 CB1R 结合的变化相关联。
总共研究了 28 只雄性 Wistar 大鼠。使用 FOCUS-220 断层扫描仪进行小动物 PET，使用 [(18)F]MK-9470。生成基于标准摄取值 (SUV，作为 CB1R 结合的衡量标准) 的 [(18)F]MK-9470 结合的参数图像。图像以 Paxinos 空间标准化，并使用 SPM8 进行体素分析 (p(height) = 0.005；k(ext) = 200)。使用 HPLC 串联质谱检测法定量测定 AEA 含量。
急性乙醇给药增加了 NAcc 中的相对 CB1R 结合，与该区域 AEA 水平的变化呈正相关。相比之下，与基线时的大鼠相比，慢性乙醇消耗或 14 天禁欲后 NAcc 中的 AEA 水平没有显著差异。慢性乙醇消耗降低了海马体和尾壳核中的相对 CB1R 结合，而与基线相比，7 天和 14 天禁欲后同一区域的相对 CB1R 结合增加。7 天和 14 天禁欲后，眶额皮质中的相对 CB1R 结合进一步减少。海马体和额叶变化的幅度与每日乙醇摄入量高度相关。
这项研究提供了体内证据，表明急性乙醇消耗与 NAcc 中内源性大麻素信号的增强有关，这表现为 CB1R 结合和 AEA 含量的增加。此外，慢性乙醇暴露导致 CB1R 水平在海马体和尾壳核等区域出现功能障碍，在该动物模型中，2 周内即可恢复。
