δ-opioid receptor inverse agonist SYK-623 improved stress-induced learning dysfunction in mice

[Speaker] Takashi Iwai:1,3
[Co-author] Toya Okonogi:1,3, Rei Mishima:1,3, Kayoko Yoshida:1,3, Misa Oyama:1,3, Shun Watanabe:1,3, Shigeto Hirayama:2,3, Hideaki Fujii:2,3, Mitsuo Tanabe:1,3
1:Lab. Pharmacol., Sch. Pharm., Kitasato University, Japan, 2:Lab. Med. Chem., Sch. Pharm., Kitasato University, Japan, 3:Med. Res. Lab., Sch. Pharm., Kitasato University, Japan

Previously, we synthesized a new inverse agonist of δ-opioid receptor (DOR), SYK-623, which is a non-peptide small molecule. The influences of DOR inverse agonist on behaviors have not been known. In the present study, we investigated the acute and chronic effects of SYK-623 on the mice behavior and activation of brain regions by immunohistochemistry. Male ddY-mice (5-6 weeks) were treated with SYK-623 (0.2-2 mg/kg, i.p.) 60 min before behavioral studies. The learning memory behavior was assessed by the Y-maze test in normal and stressed (restrain stress 2 h/day for 6 days) mice. Mice were fixed by 4% paraformaldehyde 24 h after SYK-623 administration. The brain tissue slices were immunostainded for FosB. To assess chronic effects, SYK-623 was treated for 4 weeks. The elevated-plus maze (EPM) and forced swimming test (FST) were performed after 1 and 4 weeks of treatment. Restraint stress impaired the learning memory in the Y-maze test, and SYK-623 improved the learning impairment. This effect was inhibited by naltrindol (3 mg/kg, s.c.), an antagonist of DOR. In normal mice, SYK-623 had no effects on the learning memory. SYK-623 increased the number of FosB-positive cells in hippocampus, entorhinal cortex and medial prefrontal cortex of stressed mice, but not of normal mice, indicating the possibility of neural activation in the learning system in the stressed mice. The repeated treatment of SYK-623 in normal mice did not change percent open-arm time of the EPM and immobility time in the FST. Together, SYK-623 improved stress-induced learning dysfunction, and may not have emotional side-effects induced by its chronic treatment.

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