Ketamine metabolite HNK ameliorates anhedonia symptom in Alzheimer's disease mice

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.