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Olanzapine is an antipsychotic drug used to treat patients with schizophrenia due to its lower incidence of extrapyramidal symptoms.Previous studies have shown that olanzapine activates AMP-activated protein kinase (AMPK),and induce autophagy in SH-SYSY cell line.In this study,we investigated whether olanzapine protected against rotenone-induced neurotoxicity in PC12 cells.We showed that treatment with olanzapine increased the phosphorylation of AMPK in both dose-and time-dependent manners in PC12 cells.In addition,olanzapine activated autophagy and increased autophagic vacuoles.Furthermore,olanzapine pretreatment could protect PC12 cells from rotenone-induced apoptosis.Besides,olanzapine pretreatment could suppress the rotenone-induced depolarization of mitochondrial potential and thus protect the cells.Moreover,pretreatment with specific AMPK inhibitor compound C or with autophagy inhibitor 3-methyladenine impaired the protective effect of olanzapine on rotenone-treated PC12 cells.In summary,our results show for the first time that olanzapine ameliorates rotenone-induced injury by activating autophagy through AMPK pathway.