Impaired Spatial Memory after Ketamine Administration in Chronic Low Doses

Venâncio, Carlos; Magalhães, Ana; Antunes, Luís; Summavielle, Teresa

doi:10.2174/157015911795016912

Cited by 30 publications

(20 citation statements)

References 28 publications

(32 reference statements)

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“…In rodent models of schizophrenia, the novel object recognition task has been used as an ethologically relevant paradigm to study visual episodic memory and to assess changes in task performance that result from pharmacological intervention (Grayson et al, 2007; Venâncio et al, 2011; Rajagopal et al, 2014). The task uses the innate tendency of rodents to investigate novel objects as a way to assess recognition memory.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Phensy

Duzdabanian

Brewer

et al. 2017

Front. Behav. Neurosci.

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Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70–120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.

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Section: Discussionmentioning

confidence: 99%

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Phensy

Duzdabanian

Brewer

et al. 2017

Front. Behav. Neurosci.

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“…This interpretation is somewhat plausible as ketamine and memantine impair discrimination of two visual stimuli (Talpos et al 2012; Tang and Franklin 1983; Ward et al 2013). Ketamine also impairs acquisition of visuo-auditory conditional discrimination (Dix et al 2010) and spatial learning (Alessandri et al 1989; Lalonde and Joyal 1993), spatial memory (Alessandri et al 1989; Venâncio et al 2011), and attentional set shifting (Kos et al 2011). However, MK-801, which has been shown to disrupt learning processes (Harder et al 1998; Li et al 2011; Rapanelli et al 2013; van der Staay et al 2011), does not decrease sensitivity to reinforcer magnitude.…”

Section: Discussionmentioning

confidence: 99%

Effects of N-methyl-D-aspartate receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure

et al. 2016

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Rationale The N-methyl-D-aspartate (NMDA) receptor has been recently identified as an important mediator of impulsive choice, as assessed in delay discounting. Although discounting is independently influenced by sensitivity to reinforcer magnitude and delayed reinforcement, few studies have examined how NMDA receptor ligands differentially affect these parameters. Objectives The current study examined the effects of various NMDA receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure. Methods Following behavioral training, rats received treatments of the following NMDA receptor ligands: the uncompetitive antagonists ketamine (0, 1.0, 5.0, or 10.0 mg/kg; i.p.), MK-801 (0, 0.003, 0.01, or 0.03 mg/kg; s.c.), and memantine (0, 2.5, 5.0, or 10.0 mg/kg; i.p.), the competitive antagonist CGS 19755 (0, 5.0, 10.0, or 20.0 mg/kg; s.c.), the non-competitive NR2B subunit-selective antagonist ifenprodil (0, 1.0, 3.0, or 10.0 mg/kg; i.p), and the partial agonist D-cycloserine (0, 3.25, 15.0, or 30.0 mg/kg; s.c.). Results When an exponential model was used to describe discounting, CGS 19755 (5.0 mg/kg) increased impulsive choice without altering sensitivity to reinforcer magnitude. Conversely, ketamine (10.0 mg/kg), memantine (5.0 mg/kg), and ifenprodil (10.0 mg/kg) decreased sensitivity to reinforcer magnitude without altering impulsive choice. MK-801 and D-cycloserine did not alter delay-discounting performance, although two-way ANOVA analyses indicated D-cycloserine (15.0 mg/kg) decreased impulsive choice. Conclusions The behavioral changes observed in delay discounting following administration of NMDA receptor antagonists do not always reflect an alteration in impulsive choice. These results emphasize the utility in employing quantitative methods to assess drug effects in delay discounting.

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“…Chronic ketamine exposure disrupts appetite and weight gain in adult humans and rats (60, 61). Although 15 days of repeated ketamine significantly reduced food intake and weight gain in both adolescent and adult rats, it took longer for adolescents to show deficits than their adult counterparts (Figure 4), and both groups displayed lower bodyweights than controls throughout the experiment.…”

Section: Discussionmentioning

confidence: 99%

Repeated Ketamine Exposure Induces an Enduring Resilient Phenotype in Adolescent and Adult Rats

Parise

Alcantara

Warren

et al. 2013

Biological Psychiatry

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Background Major Depressive Disorder (MDD) afflicts up to 10% of adolescents. However, nearly 50% of those afflicted are considered non-responsive to available treatments. Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist has shown potential as a rapid-acting and long-lasting treatment for MDD in adults. Thus, the effectiveness and functional consequences of ketamine exposure during adolescence were explored. Methods Adolescent male rats (postnatal day [PD] 35) received two ketamine (0, 5, 10 or 20 mg/kg) injections, 4 hours apart, after exposure to day 1 of the forced swim test (FST). The next day, rats were re-exposed to the FST to assess ketamine-induced antidepressant-like responses. Separate groups were exposed to chronic unpredictable stress (CUS) to confirm findings from the FST. After these initial experiments, adolescent naïve rats were exposed to either 1 or 15 consecutive days (PD35–49) of ketamine (20 mg/kg) twice/daily. Ketamine's influence on behavioral reactivity to rewarding (i.e., sucrose preference) and aversive (i.e., elevated plus-maze, FST) circumstances was then assessed 2 months after treatment. To control for age-dependent effects, adult rats (PD75–89) were exposed to identical experimental conditions. Results Ketamine (20 mg/kg) reversed the CUS-induced depression-like behaviors in the FST. Repeated ketamine exposure resulted in anxiolytic- and antidepressant-like responses 2 months after drug exposure. None of the ketamine doses used were capable of inducing drug-seeking behaviors as measured by place preference conditioning. Conclusions Repeated ketamine exposure induces enduring resilient-like responses regardless of age of exposure. These findings point to ketamine, and its repeated exposure, as a potentially useful antidepressant during adolescence.

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Impaired Spatial Memory after Ketamine Administration in Chronic Low Doses

Cited by 30 publications

References 28 publications

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Effects of N-methyl-D-aspartate receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure

Repeated Ketamine Exposure Induces an Enduring Resilient Phenotype in Adolescent and Adult Rats

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