Abstract
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.
Highlights
MATERIALS AND METHODSKetamine, derived from phencyclidine classes (N-1phenycyclohexypiperidine, PCP), acts as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (Martin and Lodge, 1985) by binding to the phencyclidine site (Orser et al, 1997), and has been commonly used as a type of clinical anesthetic since the 1960s (Haas and Harper, 1992)
Our results showed that ketamine at all doses (10, 20, 40, and 80 mg/kg), whether with single [Figure 1C; F(4,55) = 1.025, p = 0.403] or multiple [Figure 1C; F(4,55) = 0.836, p = 0.508] administration, did not induce any significant differences in the time spent in the center of the open field compared to the salinetreated group
Our results showed that 6 months daily administration of 30 and 60 mg/kg ketamine increased the mRNA levels of IL-6 [Figure 7A; F(2,12) = 3.92, p = 0.048] and IL-1β [Figure 7B; F(2,12) = 4.199, p = 0.042], but decreased the mRNA levels of tumor necrosis factor-α (TNF-α) [Figure 7C; F(2,12) = 8.984, p = 0.004] as compared with the saline-treated group, using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an internal control
Summary
MATERIALS AND METHODSKetamine, derived from phencyclidine classes (N-1phenycyclohexypiperidine, PCP), acts as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (Martin and Lodge, 1985) by binding to the phencyclidine site (Orser et al, 1997), and has been commonly used as a type of clinical anesthetic since the 1960s (Haas and Harper, 1992). Ketamine can produce a psychedelic experience of incredible intensity (Strayer and Nelson, 2008). Because of these side reactions, it has become increasingly popular in recent years as a recreational drug (Lankenau et al, 2007). Another study performed with developing monkeys showed that prolonged exposure to ketamine increased cell death in brain areas (Zou et al, 2009). These findings suggested that acute and chronic ketamine administration may interfere with the central nervous system
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