Loading
Tryptophan and Brain Disorders / Neurotransmitter Receptor Influence on Behavior / Treatment of Major Depression · Journal article
The International Journal of Neuropsychopharmacology · September 1, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a preclinical mechanistic study demonstrating that acute administration of HNK enantiomers restores cognitive and affective prosocial behaviors in chronically corticosterone-treated mice, an established depression model. The restoration correlates with restoration of anterior insular cortex activation during social interaction, suggesting a neural substrate. The work is hypothesis-generating and suitable for follow-up but does not yet support clinical translation or practice change.
Preclinical mechanistic study in an animal depression model with before-after comparison. Male C57BL/6J mice; chronic corticosterone-treated mice as depression model; naïve (untreated) mice as comparator; all procedures approved by Hiroshima University Animal Care and Use Committee. Intervention: Acute administration of (2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine to corticosterone-treated mice. Compared with: Naïve mice (baseline prosocial behavior); corticosterone-treated mice without HNK treatment (depression model). Hiroshima University.
Chronic corticosterone administration abolished both cognitive preference for distressed cage mates and socially transferred allodynia, two markers of intact prosocial behavior seen in naïve mice Acute administration of either (2R,6R)-HNK or (2S,6S)-HNK to corticosterone-treated mice restored both prosocial responses Anterior insular cortex (aIC) activation during social interaction with a distressed cage mate was observed in naïve mice but absent in corticosterone-treated mice
Safety was not reported in the material analysed. Check the source before drawing any conclusion about harm.
This work is preclinical and does not directly inform clinical practice. It suggests a potential neural mechanism (aIC function) linking ketamine metabolites to prosocial cognitive restoration in depression, warranting translational and clinical investigation.
Uncontrolled, preclinical study in a mouse depression model with a mechanistic focus; demonstrates proof-of-concept for ketamine metabolites restoring prosocial behaviors but requires human clinical validation.
As stated by the source record.
This work is preclinical and does not directly inform clinical practice. It suggests a potential neural mechanism (aIC function) linking ketamine metabolites to prosocial cognitive restoration in depression, warranting translational and clinical investigation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
Abstract Background The execution of prosocial behaviors requires the ability to accurately understand and infer others’ affective states. Impairments in prosocial functioning have been shown to be associated with the pathology of several psychiatric disorders. In particular, individuals with depression exhibit reduced cognitive and affective responses to others’ emotions. These impairments may exacerbate feelings of social isolation and hinder successful reintegration into society. Aims & Objectives In this study, we analyzed changes in prosocial behaviors and the associated neural activity in mice before and after the induction of a depression-like state. We also examined the effects of ketamine metabolites on the prosocial behavioral deficits. Method All animal procedures were approved by the Animal Care and Use Committee of Hiroshima University. We used chronic corticosterone-treated male C57BL/6J mice as a model of depression. We assessed the cognitive components of prosocial functioning using the three-chamber test, which involved presenting a cage mate that had been injected with complete Freund’s adjuvant (CFA; CFA mouse) alongside an untreated cage mate (non-CFA mouse). Then, we analyzed the social preference of the experimental mouse for the CFA mouse. We also assessed emotional components by measuring the mechanical allodynia transferred socially after interaction with a CFA mouse. Furthermore, to elucidate the neural mechanisms underlying prosocial deficits in corticosterone-treated mice, we analyzed c-Fos expression in relevant brain regions following social interaction with a CFA mouse and performed fiber photometry recordings in the anterior insular cortex during social interaction. Results A significant preference for the CFA-injected cage mate and socially transferred allodynia were observed in naïve mice. However, both of these prosocial responses were abolished after the depression model was induced by chronic corticosterone administration. Furthermore, the acute administration of either (2R,6R)-hydroxynorketamine (HNK) or (2S,6S)-HNK to mice treated with corticosterone restored prosocial behaviors. Our analysis of the neural mechanisms underlying prosocial behaviors revealed that social interaction with a CFA mouse significantly activated the anterior cingulate cortex and the insular cortex (IC) in naïve mice, compared with interaction with a non-CFA mouse. In contrast, activation of the anterior IC (aIC) was not observed in corticosterone-treated mice, suggesting that reduced aIC activity may contribute to prosocial behavioral deficits. Discussion & Conclusions The aIC is a pain-associated brain region that contributes to the representation of bodily states. It is also known that its activity increases in response to observed pain in close social relationships. In our previous study, a whole-brain analysis of neuronal activation patterns following ketamine administration revealed that the aIC was particularly activated in brains treated with the (R)-enantiomer of ketamine in a mouse model of depression. Furthermore, we demonstrated that aIC activation contributes to the improvement of social cognitive behaviors induced by (R)-ketamine (Yokoyama et al., Mol Psychiatry 2024). Together with our present findings, impaired prosocial behaviors in the mouse model of depression and their recovery by HNKs may be linked to changes in aIC function, highlighting the importance of this region as a potential therapeutic target.
Taken from the source record, never inferred. Follow any of these and new work involving them reaches your briefing.