A single intraperitoneal injection of ketamine does not affect spatial working, reference memory or neurodegeneration in adult mice

Ribeiro, Patrícia; Rodrigues, Paula; Valentim, Ana M.; Antunes, Luís

doi:10.1097/eja.0b013e3283610321

Cited by 13 publications

(7 citation statements)

References 37 publications

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“…In this study we performed a baseline characterization on the sex differences of the Arc-CreER T2 × CAG-Sun1/sfGFP mice treated with ketamine and (2R,6R)-HNK. Using a test battery previously established by our group [26], we found that both ketamine and (2R,6R)-HNK did not affect memory, anxiety-like behavior, sociability, and locomotion 24 h after administration but that sex significantly influenced the mouse performance in the sociability and anxiety tests [8,[29][30][31][32]. That neither ketamine nor (2R,6R)-HNK influenced memory, sociability, nor locomotion is in line with previous findings.…”

Section: Discussionsupporting

confidence: 86%

Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration

Herzog

Mellema

Remmers

et al. 2020

IJMS

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Background: Rapid-acting antidepressants ketamine and (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) have overcome some of the major limitations of classical antidepressants. However, little is known about sex-specific differences in the behavioral and molecular effects of ketamine and (2R,6R)-HNK in rodents. Methods: We treated mice with an intraperitoneal injection of either saline, ketamine (30 mg kg−1) or (2R,6R)-HNK (10 mg kg−1). We performed a comprehensive behavioral test battery to characterize the Arc-CreERT2 × CAG-Sun1/sfGFP mouse line which enables targeted recombination in active populations. We performed a molecular study in Arc-CreERT2 × CAG-Sun1/sfGFP female mice using both immunohistochemistry and in situ hybridization. Results: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in sociability and anxiety tests. Moreover, ketamine and (2R,6R)-HNK had opposite effects in the forced swim test (FST) depending on gender. In addition, in male mice, ketamine-treated animals were less immobile compared to (2R,6R)-HNK, thus showing a different profile of the two drugs in the FST. At the molecular level we identified Bdnf mRNA level to be increased after ketamine treatment in female mice. Conclusion: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in social and anxiety behavior and a different pattern between ketamine and (2R,6R)-HNK in the FST in male and female mice. At the molecular level, female mice treated with ketamine showed an increase of Bdnf mRNA level, as previously observed in male mice.

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Section: Discussionsupporting

confidence: 86%

Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration

Herzog

Mellema

Remmers

et al. 2020

IJMS

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“…This is a similar idea to that proposed in a previous clinical study with ketamine (Abel et al, 2003). Our studies cannot exclude other mechanisms, including a generalized effect on memory, although studies using similar doses in rats (Ribeiro et al, 2013) and humans have not found that ketamine at these low doses has a specific amnesic effect (Morgan et al, 2004).…”

Section: Discussionmentioning

confidence: 73%

Distinct Neuropsychological Mechanisms May Explain Delayed- Versus Rapid-Onset Antidepressant Efficacy

Stuart

Butler

Munafò

et al. 2015

Neuropsychopharmacol

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The biochemical targets for antidepressants are relatively well established, but we lack a clear understanding of how actions at these proteins translate to clinical benefits. This study used a novel rodent assay to investigate how different antidepressant drugs act to modify affective biases that have been implicated in depression. In this bowl-digging task, rats encounter two equal value learning experiences on separate days (one during an affective manipulation and the other during control conditions). This induces an affective bias that is quantified using a preference test in which both digging substrates are presented together and the individual rats’ choices recorded. The assay can be used to measure affective biases associated with learning (when the treatment is given at the time of the experience) or examine the modification of previously acquired biases (when the treatment is administered before the preference test). The rapid-onset antidepressant ketamine, but not the delayed-onset antidepressant, venlafaxine, attenuated the previously acquired FG7142-induced negative bias following systemic administration. Venlafaxine but not ketamine induced a positive bias when administered before learning. We then used local drug infusions and excitotoxic lesions to localize the effects of ketamine to the medial prefrontal cortex and venlafaxine to the amygdala. Using a modified protocol we also showed that positive and negative biases amplified further when the numbers of substrate–reinforcer associations are increased. We propose that this pattern of results could explain the delayed onset of action of venlafaxine and the rapid onset of action but lack of long-term efficacy seen with ketamine.

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“…A previous study reported that a single i.p. injection of ketamine at subanesthetic and anesthetic doses did not impair recognition memory or reference memory and did not cause neurodegeneration in adult mice (Ribeiro et al, 2013). Similarly, we did not observe a significant difference between the saline-treated group and each ketamine-treated group (10, 20, 40, or 80 mg/kg) after acute administration, whether with single or multiple administration.…”

Section: Discussionmentioning

confidence: 99%

Effects of Ketamine on Levels of Inflammatory Cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of Mice Following Acute or Chronic Administration

Shen

Wen

et al. 2017

Front. Pharmacol.

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Ketamine is an injectable anesthetic and recreational drug of abuse commonly used worldwide. Many experimental studies have shown that ketamine can impair cognitive function and induce psychotic states. Neuroinflammation has been suggested to play an important role in neurodegeneration. Meanwhile, ketamine has been shown to modulate the levels of inflammatory cytokines. We hypothesized that the effects of ketamine on the central nervous system are associated with inflammatory cytokines. Therefore, we set out to establish acute and chronic ketamine administration models in C57BL/6 mice, to evaluate spatial recognition memory and emotional response, to analyze the changes in the levels of the inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the mouse hippocampus, employing behavioral tests, Western blot, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunohistochemistry. Our results showed that ketamine at the dose of 60 mg/kg induced spatial recognition memory deficit and reduced anxiety-like behaviors in mice after chronic administration. Moreover, we found that ketamine increased the hippocampal levels of IL-6 and IL-1β after single, multiple and long-term administration in a dose-dependent manner. However, the expression level of TNF-α differed in the mouse hippocampus under different conditions. Single administration of ketamine increased the level of TNF-α, whereas multiple and long-term administration decreased it significantly. We considered that TNF-α expression could be controlled by a bi-directional regulatory pathway, which was associated with the dose and duration of ketamine administration. Our results suggest that the alterations in the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α may be involved in the neurotoxicity of ketamine.

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A single intraperitoneal injection of ketamine does not affect spatial working, reference memory or neurodegeneration in adult mice

Abstract: These data indicate that a single intraperitoneal injection of ketamine at subanaesthetic and anaesthetic doses does not impair working memory, reference memory or neurodegeneration in adult mice, but an intermediate dose of ketamine produces transitory hyperlocomotion.

Cited by 13 publications

References 37 publications

Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration

Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration

Distinct Neuropsychological Mechanisms May Explain Delayed- Versus Rapid-Onset Antidepressant Efficacy

Effects of Ketamine on Levels of Inflammatory Cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of Mice Following Acute or Chronic Administration

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