Abstract
To investigate the effects of ketamine on glucose uptake and glucose transporter (GLUT) expression in depressive-like mice. After HA1800 cells were treated with ketamine, 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) was added to the cells to test the effects of ketamine on glucose uptake, production of lactate, and expression levels of GLUT, ERK1/2, AKT, and AMPK. Adult female C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS), 27 CUMS mice were randomly divided into the depression, ketamine (i.p.10 mg/kg), and FR180204 (ERK1/2 inhibitor, i.p.100 mg/kg) + ketamine group. Three mice randomly selected from each group were injected with 18F-FDG at 6 h after treatment. The brain tissue was collected at 6 h after treatment for p-ERK1/2 and GLUTs. Treatment with ketamine significantly increased glucose uptake, extracellular lactic-acid content, expression levels of GLUT3 and p-ERK in astrocytes and glucose uptake in the prefrontal cortex (P < 0.05), and the immobility time was significantly shortened in depressive-like mice (P < 0.01). An ERK1/2 inhibitor significantly inhibited ketamine-induced increases in the glucose uptake in depressive-like mice (P < 0.05), as well as prolonged the immobility time (P < 0.01). The expression levels of p-ERK1/2 and GLUT3 in depressive-like mice were significantly lower than those in normal control mice (P < 0.01). Ketamine treatment in depressive-like mice significantly increased the expression levels of p-ERK1/2 and GLUT3 in the prefrontal cortex (P < 0.01), whereas an ERK1/2 inhibitor significantly inhibited ketamine-induced increases (P < 0.01).Our present findings demonstrate that ketamine mitigated depressive-like behaviors in female mice by activating the ERK/GLUT3 signal pathway, which further increased glucose uptake in the prefrontal cortex.
Highlights
To investigate the effects of ketamine on glucose uptake and glucose transporter (GLUT) expression in depressive-like mice
We found significantly increased production of lactate following treatment with 50 μM/L of ketamine relative to that of the control group, while no significance was found when compared with that following treatment with ketamine and an ERK1/2 inhibitor (FR180204; 1.85 ± 0.21 mM/g protein, P > 0.05, Fig. 1E)
Addition of an ERK1/2 inhibitor increased the immobility times of depressive-like mice treated with ketamine compared with those of depressive-like mice only treated with ketamine (92.67 ± 8.65 s, P < 0.05)
Summary
To investigate the effects of ketamine on glucose uptake and glucose transporter (GLUT) expression in depressive-like mice. An ERK1/2 inhibitor significantly inhibited ketamine-induced increases in the glucose uptake in depressive-like mice (P < 0.05), as well as prolonged the immobility time (P < 0.01). We hypothesized that ketamine may produce antidepressant effects via regulating glucose metabolism in the prefrontal cortex by increasing ERK phosphorylation levels, which would further upregulate the expression of GLUTs. Astrocytes, as local communication elements with multiple functions[16], are the most abundant cell type in the mammalian brain[17]. We used cultured astrocytes and established a mouse model of depression to investigate the effects of ketamine on glucose uptake and the expression of ERK/GLUTs in astrocytes within the prefrontal cortices of depressed mice
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