TY - JOUR
T1 - Organophosphate Agent Induces ADHD-Like Behaviors via Inhibition of Brain Endocannabinoid-Hydrolyzing Enzyme(s) in Adolescent Male Rats
AU - Ito, Yuki
AU - Tomizawa, Motohiro
AU - Suzuki, Kazutaka
AU - Shirakawa, Yuichi
AU - Ono, Hiromasa
AU - Adachi, Keishi
AU - Suzuki, Himiko
AU - Shimomura, Kenji
AU - Nabeshima, Toshitaka
AU - Kamijima, Michihiro
N1 - Funding Information:
This work was funded by the Uehara Memorial Foundation in 2012 and, in part, by JSPS KAKENHI (16K09102 and 19H03888).
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/2/26
Y1 - 2020/2/26
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jafc.9b08195
DO - 10.1021/acs.jafc.9b08195
M3 - Article
C2 - 31995978
AN - SCOPUS:85081004720
VL - 68
SP - 2547
EP - 2553
JO - Journal of Agricultural and Food Chemistry
JF - Journal of Agricultural and Food Chemistry
SN - 0021-8561
IS - 8
ER -