Rapid behavioral actions of ketamine require mTOR signaling. Rapamycin was infused (0.2 nmol, ICV) 30 min prior to ketamine (10 mg/kg, ip), and responses in the FST (A), NSFT (B), or LH (C) paradigms was determined. Infusion of rapamycin (0.01 nmol) into the medial prefrontal cortex (PFC) blocked the antidepressant actions of ketamine (10 mg/kg, ip) in the FST (D) and NSFT (E). (F) Location of rapamycin infusions in the PFC (infusion sites are the same on the right and left sides due to the use of bilateral cannulae). Pre-treatment with inhibitors of ERK (U0126, 20 nmol, ICV) or PI3 kinase/Akt (LY294002, 20 nmol, ICV) blocked the behavioral effects of ketamine in FST (G) and NSFT (H). (I) Low (10 mg/kg) but not a high anesthetic dose (80 mg/kg) of ketamine produced an antidepressant action in the FST. Values represent mean ± SEM (n = 6–8 animals; *P < 0.05; **P < 0.01, ANOVA).