Extended Data Figure 5. Acute and sustained antidepressant and anti-anhedonic effects of (2R,6R)- and (2S,6S)-hydroxynorketamine.

a, A single injection of (2R,6R)-HNK resulted in dose-dependent antidepressant-like responses in the learned helplessness test at the doses of 5-75 mg/kg. b, A single injection of (2S,6S)-hydroxynorketamine (HNK) induced antidepressant-like effects in the learned helplessness test at the dose of 75 mg/kg. c, Administration of (2R,6R)-HNK induced dose-dependent antidepressant effects in the 1- and 24-hour forced-swim test. d, Administration of (2S,6S)-HNK at the dose of 25 mg/kg induced antidepressant effects in the 1- and 24-hour forced-swim test. e, Despite the greater antidepressant efficacy of (2R,6R)-HNK, administration of (2S,6S)-HNK (HNK) results in higher brain hydroxynorketamine levels compared to (2R,6R)-HNK. f, (2R,6R)-HNK manifested dose-dependent antidepressant-like effects in the novelty-suppressed feeding test. g, Similar to (R,S)-ketamine (KET), the antidepressant-like effects of (2R,6R)-HNK in the forced-swim test persisted for at least 3 days post-treatment. h, A single administration of (2R,6R)-HNK reversed chronic corticosterone-induced decreases in sucrose preference. i, A single administration of (2R,6R)-HNK reversed chronic corticosterone-induced decrease in female urine sniffing preference, specifically in mice that developed an anhedonic phenotype. Administration of (2R,6R)-HNK was not associated with changes in j, locomotor activity or k, total compartmental crosses in the social interaction test following chronic social defeat stress. Data are means ± S.E.M. *p<0.05, **p<0.01, ***p<0.001. SAL, saline (statistical analyses and n numbers see Supplementary Information Table 1).