Prophylactic (R,S)-Ketamine and (2S,6S)-Hydroxynorketamine Decrease Fear Expression by Differentially Modulating Fear Neural Ensembles.
Biological Psychiatry May 1, 2025 Alessia Mastrodonato, Michelle Jin, Noelle Kee et al. 5 citations
A single injection of (R,S)-ketamine or its metabolite (2S,6S)-hydroxynorketamine (HNK) given one week before stress attenuated learned fear in male mice. The drugs altered neural activity in distinct and overlapping brain regions: (2S,6S)-HNK affected dorsal CA3, while both drugs changed activity in ventral CA3, CA1, infralimbic and prelimbic cortex, insular cortex, retrosplenial cortex, piriform cortex, nucleus reuniens, and periaqueductal gray. (R,S)-ketamine uniquely affected the paraventricular nucleus of the thalamus. (R,S)-ketamine increased connectivity between cortical and subcortical regions, whereas (2S,6S)-HNK increased connectivity within those regions. The findings identify novel fear network nodes that could be targeted to treat fear-induced disorders.