Organophosphate Agent Induces ADHD-Like Behaviors via Inhibition of Brain Endocannabinoid-Hydrolyzing Enzyme(s) in Adolescent Male Rats

Yuki Ito, Motohiro Tomizawa, Kazutaka Suzuki, Yuichi Shirakawa, Hiromasa Ono, Keishi Adachi, Himiko Suzuki, Kenji Shimomura, Toshitaka Nabeshima, Michihiro Kamijima

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Abstract

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.

Original languageEnglish
Pages (from-to)2547-2553
Number of pages7
JournalJournal of Agricultural and Food Chemistry
Volume68
Issue number8
DOIs
Publication statusPublished - 26-02-2020

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Agricultural and Biological Sciences(all)

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    Ito, Y., Tomizawa, M., Suzuki, K., Shirakawa, Y., Ono, H., Adachi, K., Suzuki, H., Shimomura, K., Nabeshima, T., & Kamijima, M. (2020). Organophosphate Agent Induces ADHD-Like Behaviors via Inhibition of Brain Endocannabinoid-Hydrolyzing Enzyme(s) in Adolescent Male Rats. Journal of Agricultural and Food Chemistry, 68(8), 2547-2553. https://doi.org/10.1021/acs.jafc.9b08195