Ketamine Metabolites Promote Anxiolysis and Hydrocortisone Stress Buffering in Zebrafish.
Jeffrey R Kelly, Lindsey S Brasfield, Aryssa H Kelsey, Grace E Seal
Behavioural brain research July 9, 2026 Peer reviewed DOI: 10.1016/j.bbr.2026.116230 via PubMed
Summary
RANK, a metabolite of ketamine, showed significant anxiolytic-like effects in zebrafish, reducing bottom-dwelling and erratic movements under normal conditions. In contrast, SHANK increased anxiety-like behavior. Both metabolites helped reduce hyperarousal caused by hydrocortisone, but only RANK consistently exhibited anxiolytic effects across different conditions. This study highlights the differing impacts of hydroxynorketamine isomers on anxiety and stress responses.
Study at a glance
| Design | experimental study |
|---|---|
| Population | zebrafish |
| Key finding | RANK produced consistent anxiolytic-like effects, while SHANK increased anxiety-like behavior under baseline conditions. |
Abstract
Anxiety and stress-related disorders affect over 280 million individuals worldwide and remain inadequately treated by current pharmacotherapies, which are often limited in efficacy and tolerability. Ketamine produces rapid therapeutic effects in mood and anxiety disorders, but its clinical use is constrained by dissociative side effects and abuse liability. Ketamine metabolites, particularly (2 R,6 R)-hydroxynorketamine (RANK) and (2S,6S)-hydroxynorketamine (SHANK), may retain therapeutic benefits while minimizing adverse effects, but their behavioral and stress-dependent actions remain incompletely understood. In the present study, we used zebrafish to examine stereospecific behavioral effects of hydroxynorketamine isomers under baseline and hydrocortisone-induced stress conditions. Behavior was assessed using the novel tank diving test alongside measures of locomotor activity and erratic movement. Under baseline conditions, RANK produced a robust anxiolytic-like profile, characterized by reduced bottom-dwelling and decreased erratic movements, whereas SHANK increased anxiety-like behavior, reflected by increased bottom-dwelling and prolonged latency to ascend. Hydrocortisone exposure induced a hyperarousal phenotype marked by increased locomotion and erratic movements without altering classical anxiety-like measures. Pretreatment with either RANK or SHANK attenuated hydrocortisone-induced hyperarousal, restoring behavior toward control levels; however, only RANK produced consistent anxiolytic-like effects across conditions. These findings demonstrate stereospecific and context-dependent behavioral effects of hydroxynorketamine isomers and highlight their differential modulation of baseline anxiety-like behavior and stress-induced hyperarousal.