%0 Journal Article %A Miwako Shobo %A Yuji Kondo %A Hiroshi Yamada %A Takuma Mihara %A Noriyuki Yamamoto %A Masaaki Katsuoka %A Katsuya Harada %A Keni Ni %A Nobuya Matsuoka %T Norzotepine, a major metabolite of zotepine, exerts atypical antipsychotic-like and antidepressant-like actions through its potent inhibition of norepinephrine reuptake %D 2010 %R 10.1124/jpet.110.166264 %J Journal of Pharmacology and Experimental Therapeutics %P jpet.110.166264 %X The antipsychotic drug zotepine (ZTP) is known to have not only atypical antipsychotic effects but also antidepressive effects in schizophrenia patients. Norzotepine (norZTP) has been postulated to be a major metabolite of ZTP in humans. Here, we characterized norZTP through several in vitro studies and in animal models of psychosis, depression, and extrapyramidal symptom (EPS), and compared the pharmacological profiles with those of ZTP. While both compounds showed similar overall neurotransmitter receptor binding profiles, norZTP showed 7-16 fold more potent norepinephrine reuptake inhibition than ZTP. In pharmacokinetic study, both ZTP and norZTP showed good brain permeability when administered individually in mice, although norZTP was not detected in plasma or brain after intraperitoneal (i.p.) injection of ZTP. In the methamphetamine-induced hyperlocomotion test in mice, norZTP and ZTP showed similar antipsychotic-like effects at doses above 1 mg/kg (i.p.). In contrast, unlike ZTP, norZTP did not induce catalepsy up to 10 mg/kg (i.p.). NorZTP significantly antagonized the hypothermia induced by reserpine, suggesting in vivo inhibition of the norepinephrine transporter. In the forced swim test, norZTP exerted an antidepressant-like effect at the effective doses for its antipsychotic action, while ZTP neither antagonized reserpine-induced hypothermia nor showed antidepressant-like effect. These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. Given that norZTP is the major metabolite observed in humans, norZTP may contribute to the unique clinical profiles of its mother compound, ZTP.The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/early/2010/03/11/jpet.110.166264.full.pdf