Ketamine metabolite HNK ameliorates anhedonia symptom in Alzheimer's disease mice.
Shuo Yang, Baihong Guo, Di Deng, Yujie Zhang, Qiang Zhou
Biochemical and Biophysical Research Communications September 17, 2026 DOI: 10.1016/j.bbrc.2026.154535 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | APP/PS1 mice at 8 months of age, a model of Alzheimer's disease |
| Interventions | (2R 6R)-hydroxynorketamine (HNK) |
| Dose | single dose |
| Measures | sucrose preference test |
| Topics | Esketamine Ketamine |
| Keywords | Alzheimer's disease Anhedonia Excitatory/inhibitory ratio Sucrose preference test |
| Key points | A single dose of the ketamine metabolite (2R,6R)-hydroxynorketamine rapidly reduced anhedonia in 8-month-old APP/PS1 mice, as measured by the sucrose preference test. The authors propose this effect is mediated by an increased prefrontal excitatory/inhibitory ratio, reduced phosphorylated eEF2, and elevated BDNF and GLT-1 expression, suggesting HNK as a candidate treatment for anhedonia in Alzheimer's disease. |
Abstract
Anhedonia is frequently observed in Alzheimer's disease (AD) patients and is associated with a higher risk of cognitive decline and dementia, and it potentially serve as preclinical marker and psychopathological risk factor for AD. Current antidepressants show limited efficacy in anhedonia, highlighting a critical unmet medical need. In this study, APP/PS1 mice at 8 months of age exhibited pronounced anhedonia symptom, as assessed by the sucrose preference tests. Strikingly, a single dose of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) rapidly alleviated this symptom. Mechanistically, HNK increased the prefrontal excitatory/inhibitory (E/I) ratio via enhanced activity in the excitatory neurons, accompanied by reduced phosphorylated eEF2 levels and elevated BDNF and GLT-1 expression. These findings indicate that HNK ameliorates anhedonia in AD mice via mechanisms similar to those shown in standalone depression, and hence offers a promising therapeutic intervention worthy of further pursuing.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 5
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry 2018
- Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression Frontiers in Psychiatry October 18, 2021
- The Use of Ketamine for the Treatment of Anhedonia in Depression. CNS Drugs August 1, 2024
- BDNF-TrkB signaling-mediated upregulation of Narp is involved in the antidepressant-like effects of (2R,6R)-hydroxynorketamine in a chronic restraint stress mouse model BMC Psychiatry March 15, 2022