Ketamine Metabolites Promote Anxiolysis and Hydrocortisone Stress Buffering in Zebrafish.
Behavioural brain research July 9, 2026 Jeffrey R Kelly, Lindsey S Brasfield, Aryssa H Kelsey et al.
Hydroxynorketamine isomers have stereospecific and context-dependent effects on anxiety-like behavior and stress-induced hyperarousal in zebrafish. Under baseline conditions, (2R,6R)-hydroxynorketamine (RANK) produced a robust anxiolytic-like profile, reducing bottom-dwelling and erratic movements, whereas (2S,6S)-hydroxynorketamine (SHANK) increased anxiety-like behavior, shown by more bottom-dwelling and longer latency to ascend. Hydrocortisone exposure induced a hyperarousal phenotype with increased locomotion and erratic movements but no change in classical anxiety measures. Pretreatment with either RANK or SHANK attenuated this hyperarousal, restoring behavior toward control levels, but only RANK produced consistent anxiolytic-like effects across conditions.