Effects of a single injection of (R)-ketamine, (R)-norketamine, and (2R,6R)- HNK in a rat LH model. (A) Rats received inescapable electric shock (IES) treatments on 2 days (days 1 and 2), passed a post-shock test (PS) on day 3, and were designated as learned helplessness (LH) rats with depression-like phenotype. On day 3, vehicle (saline: 2 mL/kg), (R)-ketamine (20 mg/kg), (R)-norketamine (20 mg/kg), or (2R,6R)- HNK (20 and 40 mg/kg) was administered i.p. into LH rats. On day 8 (5 days after a single injection), conditioned avoidance (CA) test to study the antidepressant effect was performed. (B) The failure number of LH (1-way ANOVA: F_4,24 = 3.755, P = .0167). The escape latency of LH (1-way ANOVA: F_4,24 = 3.973, P = .013). Data are shown as mean ± SEM (n = 5–8). The number in the parenthesis is the dose (mg/kg). *P < .05 compared with vehicle-treated group. (C) Rats received IES treatments on 2 days (days 1 and 2), passed a PS on day 3, and were designated as LH rats with depression-like phenotype. On day 3, either vehicle (saline: 2 mL/kg), (R)-ketamine (20 mg/kg), or (2R,6R)- HNK (20 mg/kg) was administered i.p. into LH rats. CA test was performed on day 4 (24 hours after a single injection). (D) The failure number of LH (1-way ANOVA: F_2,14 = 13.52, P < .0001). The escape latency of LH (1-way ANOVA: F_2,14 = 14.73, P = .0004). Data are shown as mean ± SEM (n = 5 or 6). The number in the parenthesis is the dose (mg/kg). **P < .01, ***P < .001 compared with vehicle-treated group. R-KT: (R)-ketamine, R-NKT: (R)-norketamine, R-HNK: (2R,6R)-hydroxynorketamine.