Enhancement of anandamide formation in the limbic forebrain and reduction of endocannabinoid contents in the striatum of Δ9-tetrahydrocannabinol-tolerant rats
Enhancement of anandamide formation in the limbic forebrain and reduction of endocannabinoid contents in the striatum of Δ9-tetrahydrocannabinol-tolerant rats
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DOI：
10.1046/j.1471-4159.2000.0741627.x
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发表时间：
2000-04-01
影响因子：
4.7
通讯作者：
Fernández-Ruiz, JJ
中科院分区：
文献类型：
--
作者：
Di Marzo, V;Berrendero, F;Fernández-Ruiz, JJ
最近的研究表明，成年大鼠长期接触合成或植物源性大麻素后观察到的药理学耐受性伴随着脑大麻素受体的下调/脱敏。然而，没有证据表明大麻素耐受大鼠大脑中大麻素受体内源配体的含量可能发生变化。本研究旨在阐明这种可能性，通过同位素稀释气相色谱/质谱法测量每天接受 10 mg 治疗的成年雄性大鼠的几个脑区中花生四烯酸乙醇酰胺（花生四烯酰乙醇酰胺；AEA）及其生物合成前体 N-花生四烯酰磷脂酰乙醇胺（NArPE）和 2-花生四烯酰甘油（2-AG）的含量。 Delta(9)-四氢大麻酚 (Delta(9)-THC)，为期 8 天。分析的区域包括小脑、纹状体、边缘前脑、海马、大脑皮层和脑干。还分析了相同区域的大麻素受体结合和 WIN-55,212-2 刺激的鸟苷基-5'-O-(gamma-[S-35]thio)-三磷酸 ([S-35]GTP gamma S) 结合，以测试众所周知的下调/脱敏现象的发展。结果如下： 正如预期的那样，大麻素受体结合和 WIN-55,212-2 刺激的 [S-35]GTP gamma S 结合在 Delta(9)-THC 耐受大鼠的大部分脑区中减少。唯一在这两个参数上都没有变化的区域是边缘前脑。经过 Delta(9)-THC 处理 8 天后，同一区域的 AEA 含量显着（几乎四倍）增加。相比之下，纹状体的 AEA 含量下降，而脑干、海马、小脑或大脑皮层则没有发现变化。在边缘前脑中观察到的 AEA 含量增加伴随着 NArPE 水平下降的趋势，而在纹状体中，NArPE 含量没有发现显着变化。 Delta(9)-THC 耐受大鼠大脑区域中 2-AG 的含量没有变化，但纹状体中的 2-AG 含量显着下降。总之，目前的结果表明，大麻素受体的长时间激活会导致纹状体中内源性大麻素含量和信号传导减少，并导致边缘前脑中 AEA 形成增加。鉴于内源性大麻素在控制运动行为和情绪状态中的作用，讨论了这些发现的病理生理学意义。
Recent studies have shown that the pharmacological tolerance observed after prolonged exposure to synthetic or plant-derived cannabinoids in adult rats is accompanied by down-regulation/desensitization of brain cannabinoid receptors. However, no evidence exists on possible changes in the contents of the endogenous ligands of cannabinoid receptors in the brain of cannabinoid-tolerant rats. The present study was designed to elucidate this possibility by measuring, by means of isotope dilution gas chromatography/mass spectrometry, the contents of both anandamide (arachidonoylethanolamide; AEA) and its biosynthetic precursor, N-arachidonoylphosphatidylethanolamine (NArPE), and 2-arachidonoylglycerol (2-AG) in several brain regions of adult male rats treated daily with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) for a period of 8 days. The areas analyzed included cerebellum, striatum, limbic forebrain, hippocampus, cerebral cortex, and brainstem. The same regions were also analyzed for cannabinoid receptor binding and WIN-55,212-2-stimulated guanylyl-5'-O-(gamma-[S-35]thio)-triphosphate ([S-35]GTP gamma S) binding to test the development of the well known down-regulation/desensitization phenomenon. Results were as follows: As expected, cannabinoid receptor binding and WIN-55,212-2-stimulated [S-35]GTP gamma S binding decreased in most of the brain areas of Delta(9)-THC-tolerant rats. The only region exhibiting no changes in both parameters was the limbic forebrain. This same region exhibited a marked (almost fourfold) increase in the content of AEA after 8 days of Delta(9)-THC treatment. By contrast, the striatum exhibited a decrease in AEA contents, whereas no changes were found in the brainstem, hippocampus, cerebellum, or cerebral cortex. The increase in AEA contents observed in the limbic forebrain was accompanied by a tendency of NArPE levels to decrease, whereas in the striatum, no significant change in NArPE contents was found. The contents of 2-AG were unchanged in brain regions from Delta(9)-THC-tolerant rats, except for the striatum where they dropped significantly. In summary, the present results show that prolonged activation of cannabinoid receptors leads to decreased endocannabinoid contents and signaling in the striatum and to increased AEA formation in the limbic forebrain. The pathophysiological implications of these findings are discussed in view of the proposed roles of endocannabinoids in the control of motor behavior and emotional states.