Department of Occupational and Environmental Health , Nagoya City University Graduate School of Medical Sciences , Nagoya 467-8601 , Japan.
Department of Chemistry, Faculty of Life Sciences , Tokyo University of Agriculture , Setakaya , Tokyo 156-8502 , Japan.
J Agric Food Chem. 2020 Feb 26;68(8):2547-2553. doi: 10.1021/acs.jafc.9b08195. Epub 2020 Feb 13.
Anticholinergic organophosphate (OP) agents act on the diverse serine hydrolases, thereby revealing unexpected biological effects. Epidemiological studies indicate a relationship between the OP exposure and development of attention-deficit/hyperactivity disorder (ADHD)-like symptoms, whereas no plausible mechanism for the OP-induced ADHD has been established. The present investigation employs ethyl octylphosphonofluoridate (EOPF) as an OP-probe, which is an extremely potent inhibitor of endocannabinoid (EC, anandamide and 2-arachidonoylglycerol)-hydrolyzing enzymes: that is, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). An ex vivo experiment shows that EOPF treatment decreases FAAH and MAGL activities and conversely increases EC levels in the rat brain. Subsequently, EOPF (treated intraperitoneally once at 0, 1, 2, or 3 mg/kg) clearly induces ADHD-like behaviors (in elevated plus-maze test) in both Wistar and spontaneously hypertensive rats. The EOPF-induced behaviors are reduced by a concomitant administration of cannabinoid receptor inverse agonist SLV-319. Accordingly, the EC system is a feasible target for OP-caused ADHD-like behaviors in adolescent rats.
拟胆碱能有机磷 (OP) 类药物作用于多种丝氨酸水解酶，从而揭示出意想不到的生物学效应。 流行病学研究表明，OP 暴露与注意力缺陷/多动障碍 (ADHD) 样症状的发展之间存在关系，而尚未建立 OP 诱导 ADHD 的合理机制。 本研究采用乙基辛基膦酸氟化物 (EOPF) 作为 OP 探针，它是内源性大麻素 (EC，大麻素和 2-花生四烯酰甘油) 水解酶的极其有效的抑制剂：即脂肪酸酰胺水解酶 (FAAH) 和单酰基甘油脂肪酶 (MAGL)。 一项离体实验表明，EOPF 处理降低了大鼠脑中 FAAH 和 MAGL 的活性，而 EC 水平则相反增加。 随后，EOPF（在 0、1、2 或 3 mg/kg 时一次性腹膜内给药）在 Wistar 和自发性高血压大鼠中均明显诱导出 ADHD 样行为（高架十字迷宫测试）。 大麻素受体反向激动剂 SLV-319 的伴随给药可降低 EOPF 诱导的行为。 因此，EC 系统是青春期大鼠 OP 引起的 ADHD 样行为的可行靶标。
