Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
Sci Rep. 2019 Jul 3;9(1):9621. doi: 10.1038/s41598-019-45969-4.
The impairment of learning and memory is a well-documented effect of both natural and synthetic cannabinoids. In the present study, we aimed to investigate the effect of acute administration of JWH-018, a synthetic cannabinoid, on the hippocampal metabolome to assess biochemical changes in vivo. JWH-018 elevated levels of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The increase of endocannabinoid levels in response to JWH-018 could be inhibited by co-administration of AM251, a CB1 receptor antagonist. Biochemical analyses revealed that this was the result of suppression of two hydrolases involved in endocannabinoid degradation (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL]). Additionally, we showed that JWH-018 causes a reduction in the levels of brain-derived neurotrophic factor (BDNF), which is known to modulate synaptic plasticity and adaptive processes underlying learning and memory. The decrease of BDNF following JWH-018 treatment was also rescued by co-administration of AM251. As both endocannabinoids and BDNF have been shown to modulate learning and memory in the hippocampus, the alteration of their levels in response to JWH-018 may explain the contribution of synthetic cannabinoids to impairment of memory.
学习和记忆的损伤是天然和合成大麻素的一个众所周知的作用。在本研究中，我们旨在研究急性给予合成大麻素 JWH-018 对海马代谢组的影响，以评估体内的生化变化。JWH-018 升高了内源性大麻素，即花生四烯酸乙醇胺（AEA）和 2-花生四烯酰甘油（2-AG）的水平。内源性大麻素水平的增加可以通过共同给予 CB1 受体拮抗剂 AM251 来抑制。生化分析表明，这是两种参与内源性大麻素降解的水解酶（脂肪酸酰胺水解酶 [FAAH] 和单酰基甘油脂肪酶 [MAGL]）受到抑制的结果。此外，我们表明 JWH-018 导致脑源性神经营养因子（BDNF）水平降低，BDNF 已知调节学习和记忆的突触可塑性和适应性过程。JWH-018 处理后 BDNF 的减少也可以通过共同给予 AM251 来挽救。由于内源性大麻素和 BDNF 都被证明可以调节海马体中的学习和记忆，因此它们对 JWH-018 的反应水平的改变可能解释了合成大麻素对记忆损伤的贡献。
