Caberlotto Laura, Rimondini Roberto, Hansson Anita, Eriksson Siv, Heilig Markus
Division of Psychiatry, NEUROTEC, Karolinska Institute, Stockholm, Sweden.
Neuropsychopharmacology. 2004 Jan;29(1):15-22. doi: 10.1038/sj.npp.1300296.
Chronic treatment with cannabinoid agonists leads to tolerance. One possible mechanism for this is receptor internalization, but tolerance has also been reported with compounds that only cause internalization to a low degree. Furthermore, cannabinoid antagonist administration precipitates a characteristic withdrawal syndrome in tolerant subjects, accompanied by neuronal activation and enhanced release of corticotropin-releasing hormone (CRH) in the central amygdala. The underlying molecular mechanisms are unknown. We examined the role of cannabinoid tolerance and withdrawal for the expression of the cannabinoid 1 (CB1) receptor and of CRH in rats. Tolerance was first established functionally. An acute dose (100 microg/kg) of the CB1 agonist HU-210 suppressed locomotor activity, and had an anxiogenic-like effect on the elevated plus-maze. Both effects were absent following daily treatment with the same agonist or a lower (40 microg/kg) dose for 14 days. Next, withdrawal was reliably precipitated by a single dose (3 mg/kg) of the CB1 antagonist SR141716A in rats treated subchronically with 14-day HU-210. Using in situ hybridization, a robust suppression of CB1 mRNA expression was found in the caudate-putamen, indicating a downregulation of CB1 expression levels as one mechanism for tolerance to the locomotor suppressant effects of HU-210. The CRH transcript was upregulated in the central amygdala in precipitated withdrawal compared to nonwithdrawn tolerant subjects, suggesting that increased gene expression contributes to the previously reported CRH release in withdrawal. Most importantly, this increase occurred from a suppressed level in tolerant subjects, and behavioral signs of withdrawal, presumably mediated by CRH, were seen at the CRH expression that had only returned to normal nontolerant levels. This suggests the possibility of an allostatic shift, as previously proposed on theoretical grounds. The expression of CRH-R1, CRH-R2alpha, NPY, and its Y1 receptor mRNA was analyzed in search of neural substrates for the allostatic shift observed, but did not seem to contribute to the dysregulated state.
大麻素激动剂的长期治疗会导致耐受性。一种可能的机制是受体内化，但据报道，对于那些仅能引起低程度内化的化合物也会出现耐受性。此外，在耐受性受试者中，给予大麻素拮抗剂会引发一种特征性的戒断综合征，同时伴有神经元激活以及中央杏仁核中促肾上腺皮质激素释放激素（CRH）的释放增加。其潜在的分子机制尚不清楚。我们研究了大麻素耐受性和戒断在大鼠大麻素1（CB1）受体及CRH表达中的作用。首先从功能上建立耐受性。急性剂量（100微克/千克）的CB1激动剂HU - 210可抑制运动活性，并对高架十字迷宫产生类似焦虑的作用。在用相同激动剂或较低剂量（40微克/千克）每日治疗14天后，这两种作用均消失。接下来，在经14天HU - 210亚慢性治疗的大鼠中，单次剂量（3毫克/千克）的CB1拮抗剂SR141716A可可靠地引发戒断反应。通过原位杂交发现，尾状核 - 壳核中CB1 mRNA表达受到强烈抑制，这表明CB1表达水平下调是对HU - 210运动抑制作用产生耐受性的一种机制。与未戒断的耐受性受试者相比，在戒断反应中中央杏仁核中的CRH转录本上调，这表明基因表达增加导致了先前报道的戒断时CRH释放增加。最重要的是，这种增加是从耐受性受试者中受抑制的水平开始的，并且在CRH表达仅恢复到正常非耐受性水平时就出现了可能由CRH介导的戒断行为迹象。这表明存在如先前基于理论提出的适应性负荷转移的可能性。为了寻找观察到的适应性负荷转移的神经基础，我们分析了CRH - R1、CRH - R2α、NPY及其Y1受体mRNA的表达，但它们似乎并未导致失调状态。
