Extended Data Figure 5: Acute and sustained antidepressant and anti-anhedonic effects of (2R,6R)- and (2S,6S)-HNK.
From: NMDAR inhibition-independent antidepressant actions of ketamine metabolites
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−1. b, A single injection of (2S,6S)- HNK induced antidepressant-like effects in the learned helplessness test at the dose of 75 mg kg−1. c, Administration of (2R,6R)-HNK induced dose-dependent antidepressant effects in the 1- and 24-h FST. d, Administration of (2S,6S)-HNK at the dose of 25 mg kg−1 induced antidepressant effects in the 1- and 24-h FST. 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 NSF test. g, Similar to (R,S)-KET, the antidepressant-like effects of (2R,6R)-HNK in the FST persisted for at least 3 days after 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 locomotor activity (j) or total compartmental crosses in the social interaction test after chronic social defeat stress (k). Data are mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001 (see Supplementary Table 1 for statistical analyses and n numbers).
