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

Highlights

• (R)-ketamine improved PCP-induced cognitive deficits in mice.

• (S)-ketamine did not improve PCP-induced cognitive deficits in mice.

• TrkB inhibitor blocked the effects of (R)-ketamine in PCP model.

• (R)-ketamine would be a therapeutic drug for cognitive impairment.

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.

Introduction

Cognitive impairment is a core symptom in patients with schizophrenia; however, there are no therapeutic drugs for cognitive impairment in these patients (Goff et al., 2011; Green, 1996; Hashimoto, 2019a). Multiple lines of evidence suggest that the N-methyl-d-aspartate receptor (NMDAR) hypofunction might be involved in the several symptoms including cognitive impairment in schizophrenia (Coyle, 2017; Hashimoto et al., 2013; Hashimoto, 2014; Javitt and Zukin, 1991; Lin et al., 2019; Lin and Lane, 2019; Nakazawa and Sapkota, 2019). The NMDAR antagonist phencyclidine (PCP) is known to induce schizophrenia-like symptoms including cognitive impairment in healthy subjects (Javitt and Zukin, 1991; Domino and Luby, 2012; Javitt et al., 2012). Therefore, PCP-treated rodents have been used as an animal model of schizophrenia (Hashimoto et al., 2005, Hida et al., 2015; Hashimoto et al., 2008; Hida et al., 2015; Jentsch and Roth, 1999; Morris et al., 2005; Shirai et al., 2015; Yoshimi et al., 2014). Our study using the novel object recognition test (NORT) demonstrated that PCP-induced cognitive deficits could be ameliorated by subsequent repeated administration of clozapine, but not haloperidol (Hashimoto et al., 2005). Thus, it is possible that the reversal of PCP-induced cognitive deficits might be a potential animal model of clozapine-like antipsychotic activity (Hashimoto et al., 2005).

The NMDAR antagonist (R,S)-ketamine is also known to produce schizophrenia-like symptoms including cognitive impairment in healthy subjects (Domino, 2010; Krystal et al., 1994). However, in the mood disorder research, (R,S)-ketamine is the most attractive antidepressant since (R,S)-ketamine produces rapid-acting and sustained antidepressant effects in treatment-resistant depressed patients (Chaki, 2017; Duman, 2018; Hashimoto, 2019b; Krystal et al., 2019; ; C. Yang et al., 2019; Zanos et al., 2018; Zhang and Hashimoto, 2019). (R,S)-ketamine is a racemic mixture containing equal amount of (R)-ketamine and (S)-ketamine. (S)-ketamine has an approximately 4-fold greater affinity for the NMDAR than (R)-ketamine (Domino, 2010; Hashimoto, 2019b). On March 5, 2019, the United State Food and Drug Administration approved (S)-ketamine nasal spray in conjunction with an oral antidepressant for peoples with treatment-resistant depression. However, there are several concerns regarding the efficacy and the safety of (S)-ketamine (Jauhar and Morrison, 2019; Kaur et al., 2019; McShane et al., 2019; Turner, 2019).

In contrast, (R)-ketamine has the beneficial effects compared with (S)-ketamine in several animal models such as depression (Fukumoto et al., 2017; Yang et al., 2015, Yang et al., 2018; Zanos et al., 2016; Zhang et al., 2014) and Parkinson's disease (Fujita et al., 2019). Furthermore, brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin kinase B (TrkB) signaling might play a role in the beneficial effects of (R)-ketamine (Fujita et al., 2019; Yang et al., 2015, Yang et al., 2018). However, there are no reports examining the effects of ketamine enantiomers in PCP-induced cognitive deficits in rodents.

In this study, using the NORT, we investigated the effects of subsequent repeated intermittent administration of two ketamine enantiomers on PCP-induced cognitive deficits in mice. Furthermore, we investigated the role of BDNF-TrkB signaling in the beneficial effects of (R)-ketamine in the PCP-induced model.