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.

Abstract

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 mg/kg/day for 10 days)-induced cognitive deficits were ameliorated by subsequent repeated intermittent administration of (R)-ketamine (10 mg/kg/day, 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-TrkB/TrkB 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.

• Authors: Yunfei Tan, Yuko Fujita, Youge Qu, Lijia Chang, Yaoyu Pu, Siming Wang, Xingming Wang, Kenji Hashimoto
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 188 Pg. 172839 (01 2020) ISSN: 1873-5177 [Electronic] United States
• PMID: 31866390 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Bdnf protein, mouse
• Brain-Derived Neurotrophic Factor
• Excitatory Amino Acid Antagonists
• Membrane Glycoproteins
• Ketamine
• Ntrk2 protein, mouse
• Protein-Tyrosine Kinases
• Phencyclidine

Topics

• Allosteric Regulation (drug effects, physiology)
• Animals
• Brain-Derived Neurotrophic Factor (antagonists & inhibitors, metabolism)
• Cognition Disorders (chemically induced, drug therapy, metabolism)
• Drug Administration Schedule
• Excitatory Amino Acid Antagonists (administration & dosage)
• Ketamine (administration & dosage)
• Male
• Membrane Glycoproteins (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred ICR
• Phencyclidine (toxicity)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects, physiology)