Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Neuropsychopharmacology. 2012 Nov;37(12):2624-34. doi: 10.1038/npp.2012.123. Epub 2012 Aug 1.
Biphasic effects of cannabinoids have been shown in processes such as feeding behavior, motor activity, motivational processes and anxiety responses. Using two different tests for the characterization of anxiety-related behavior (elevated plus-maze and holeboard), we first identified in wild-type C57BL/6N mice, two doses of the synthetic CB1 cannabinoid receptor agonist CP-55,940 with anxiolytic (1 μg/kg) and anxiogenic properties (50 μg/kg), respectively. To clarify the role of CB1 receptors in this biphasic effect, both doses were applied to two different conditional CB1 receptor knockout (KO) mouse lines, GABA-CB1-KO (CB1 receptor inactivation in forebrain GABAergic neurons) and Glu-CB1-KO (CB1 receptor inactivation in cortical glutamatergic neurons). We found that the anxiolytic-like effects of the low dose of cannabinoids are mediated via the CB1 receptor on cortical glutamatergic terminals, because this anxiolytic-like response was abrogated only in Glu-CB1-KO mice. On the contrary, the CB1 receptor on the GABAergic terminals is required to induce an anxiogenic-like effect under a high-dose treatment because of the fact that this effect was abolished specifically in GABA-CB1-KO mice. These experiments were carried out in both sexes, and no differences occurred with the doses tested in the mutant mice. Interestingly, the positive allosteric modulation of GABA(B) receptor with GS-39783 was found to largely abrogate the anxiogenic-like effect of the high dose of CP-55,940. Our results shed new light in further understanding the biphasic effects of cannabinoids at the molecular level and, importantly, pave the way for the development of novel anxiolytic cannabinoid drugs, which may have favorable effect profiles targeting the CB1 receptor on glutamatergic terminals.
大麻素在摄食行为、运动活动、动机过程和焦虑反应等过程中表现出双相作用。我们使用两种不同的焦虑相关行为测试（高架十字迷宫和洞板）来鉴定野生型 C57BL/6N 小鼠中的两种合成 CB1 大麻素受体激动剂 CP-55,940 的剂量，这两种剂量分别具有抗焦虑（1μg/kg）和致焦虑作用（50μg/kg）。为了阐明 CB1 受体在这种双相作用中的作用，我们将这两种剂量应用于两种不同的条件性 CB1 受体敲除（KO）小鼠品系，GABA-CB1-KO（前脑 GABA 能神经元中 CB1 受体失活）和 Glu-CB1-KO（皮质谷氨酸能神经元中 CB1 受体失活）。我们发现，低剂量大麻素的抗焦虑样作用是通过皮质谷氨酸能末梢上的 CB1 受体介导的，因为这种抗焦虑样反应仅在 Glu-CB1-KO 小鼠中被消除。相反，在高剂量治疗下，需要 GABA 能末梢上的 CB1 受体来诱导致焦虑样效应，因为这种效应仅在 GABA-CB1-KO 小鼠中被消除。这些实验在两性中进行，并且在突变小鼠中测试的剂量没有差异。有趣的是，GABA(B) 受体的正变构调节剂 GS-39783 被发现可大大消除 CP-55,940 高剂量的致焦虑样效应。我们的结果从分子水平上进一步阐明了大麻素的双相作用，并为开发新型抗焦虑大麻素药物提供了新的思路，这些药物可能针对谷氨酸能末梢上的 CB1 受体具有有利的作用谱。
