Phencyclidine-induced cognitive deficits in mice are ameliorated by subsequent repeated intermittent administration of (R)-ketamine, but not (S)-ketamine Role of BDNF-TrkB signaling.
The N-methyl-d-aspartate receptor (NMDAR) antagonists including phencyclidine (PCP) and ketamine produce cognitive deficits in rodents and humans. We previously reported that (R)-ketamine produced the beneficial effects compared to (S)-ketamine in several animal models including depression. Here we compared the effects of two enantiomers of ketamine on cognitive deficits in mice after repeated administration of PCP. PCP (10 mgkgday for 10 days)-induced cognitive deficits were ameliorated by subsequent repeated intermittent administration of (R)-ketamine (10 mgkgday, twice weekly for 2-weeks), but not (S)-ketamine. Western blot analysis showed decreased levels of brain-derived neurotrophic factor (BDNF) and decreased ratio of phosphorylated-TrkB (p-TrkB) to TrkB in the prefrontal cortex (PFC) and hippocampus of PCP-treated mice. Furthermore, PCP-induced reduction of BDNF and p-TrkBTrkB ratio in the PFC and hippocampus of PCP-treated mice was ameliorated by subsequent intermittent administration of (R)-ketamine. Interestingly, the beneficial effects of (R)-ketamine were blocked by pretreatment with TrkB inhibitor ANA-12. These findings suggest that (R)-ketamine could ameliorate PCP-induced cognitive deficits via activation of BDNF-TrkB signaling in the brain. Therefore, (R)-ketamine could be a potential therapeutic drug for cognitive impairment in patients with schizophrenia.