Ketamine Increases vmPFC Activity: Effects of (R)- and (S)-Stereoisomers and (2R,6R) Hydroxynorketamine Metabolite

Abstract Ketamine, an NMDA receptor antagonist and fast acting antidepressant, produces a rapid burst of glutamate in the ventral medial prefrontal cortex (mPFC). Preclinical studies have demonstrated that pyramidal cell activity in the vmPFC is necessary for the rapid antidepressant response to ketamine in rodents. We sought to characterize the effects of ketamine and its stereoisomers (R and S), as well as a metabolite, (2R,6R)-hydroxynorketamine (HNK), on vmPFC activity using a genetically encoded calcium indicator (GCaMP6f). Ratiometric fiber photometry was utilized to monitor GCaMP6f fluorescence in pyramidal cells of mouse vmPFC prior to and immediately following administration of compounds. GCaMP6f signal was assessed to determine correspondance of activity between compounds. We observed dose dependent effects with (R,S)-ketamine (3–100 mg/kg), with the greatest effects on GCaMP6f activity at 30 mg/kg and lasting up to 20 min. (S)-ketamine (15 mg/kg), which has high affinity for the NMDA receptor channel produced similar effects to (R,S)-ketamine, but compounds with low NMDA receptor affinity, including (R)-ketamine (15 mg/kg) and (2R,6R)-HNK (30 mg/kg) had little or no effect on GCaMP6f activity. The initial response to administration of (R,S)-ketamine as well as (S)-ketamine is characterized by a brief period of robust GCaMP6f activation, consistent with increased activity of vmPFC pyramidal neurons. Because (2R,6R)-HNK and (R)-ketamine are reported to have antidepressant activity in rodent models the current results indicate that different initiating mechanisms lead to similar brain adaptive consequences that underlie the rapid antidepressant responses.