Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model

Abstract

Accumulating evidence suggests a key role of the gut-microbiota-brain axis in the antidepressant actions of certain compounds. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, showed rapid and sustained antidepressant effects in treatment-resistant depressed patients. In contrast, another NMDAR antagonist, lanicemine, did not exhibit antidepressant effects in such patients. (R)-ketamine, the (R)-enantiomer of ketamine, has rapid-acting and long-lasting antidepressant effects in rodent models of depression. Here we compared the effects of (R)-ketamine and lanicemine on depression-like phenotype and the composition of the gut microbiota in susceptible mice after chronic social defeat stress (CSDS). In behavioral tests, (R)-ketamine showed antidepressant effects in the susceptible mice, whereas lanicemine did not. The 16S ribosomal RNA gene sequencing of feces demonstrated that (R)-ketamine, but not lanicemine, significantly attenuated the altered levels of Bacteroidales, Clostridiales and Ruminococcaceae in the susceptible mice after CSDS. At the genus level, (R)-ketamine significantly attenuated the marked increase of Clostridium in the susceptible mice. In contrast, the effects of lanicemine were less potent than those of (R)-ketamine. This study suggests that the antidepressant effects of (R)-ketamine might be partly mediated by the restoration of altered compositions of the gut microbiota in a CSDS model.

Figure 1

Effects of (R)-ketamine and lanicemine in the depression-like phenotype susceptible mice after CSDS. (a) The schedule of CSDS model, treatment, behavioral tests and feces collection. CSDS was performed from day 1 to day 10, and social interaction test (SIT) was performed on day 11. Saline (10 ml/kg), (R)-ketamine (10 mg/kg), or lanicemine (10 mg/kg) were administered i.p. into CSDS susceptible mice on day 12. Behavioral tests and SPT were performed form day 12 to day 14. On day 15, feces were collected. (b) Body weight (two-way ANOVA, time: F_3,15 = 20.99, P < 0.001, treatment: F_3,15 = 1.688, P = 0.176, interaction: F_9,15 = 0.337, P = 0.960). (c–e) Behavioral tests including LMT (one-way ANOVA, F_3,20 = 0.241, P = 0.867), TST (F_3,20 = 7.025, P = 0.002) and FST (F_3,20 = 4.722, P = 0.012) were performed. (f) SPT was performed 2 days after a single dose (F_3,20 = 9.555, P < 0.001). Data are shown as mean ± S.E.M. (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001. NS: not significant.

Figure 2

The PCoA of the gut bacterium data. The PCoA analysis plots of Bray-Curtis dissimilarity among the four groups (n = 6).

Figure 3

Composition in the gut bacterium at the levels of phylum and class. (a) The relative abundances of phylum in fecal samples of the four groups 3 days after a single dose of saline, (R)-ketamine or lanicemine. The relative abundances of Bacteroidetes and Firmicutes were shown in the all groups. (b) The relative abundances of class in fecal samples of the four groups 3 days after a single dose of saline, (R)-ketamine or lanicemine. The relative abundances of Bacteroidia, Bacilli, and Clostridia were shown in the all groups. Data of each mouse are shown (n = 6).

Figure 4

Altered composition in the gut bacteria at the order level. (a) The relative abundances of order in fecal samples of the four groups 3 days after a single dose of saline, (R)-ketamine or lanicemine. (b)The order levels of Bacteroidales were significantly altered (one-way ANOVA: F_3,20 = 45.166, P < 0.001). (c) The order level of Clostridiales were significantly altered (one-way ANOVA: F_3,20 = 30.221, P < 0.001). Data are shown as mean ± S.E.M. (n = 6). **P < 0.01, ***P < 0.001. NS: not significant.

Figure 5

Altered composition in the gut bacteria at the family level. (a) The relative abundances of family in fecal samples of the four groups 3 days after a single dose of saline, (R)-ketamine or lanicemine. (b) The family levels of Ruminococaceae were significantly altered (one-way ANOVA: F_3,20 = 32.341, P < 0.001). (c) The family levels of Mogibacteriaceae were significantly altered (one-way ANOVA: F_3,20 = 49.097, P < 0.001). Data are shown as mean ± S.E.M. (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001. NS: not significant.

Figure 6

Altered composition in the gut bacteria at the genus level. (a) The relative abundances of genus in fecal samples of the four groups 3 days after a single dose of saline, (R)-ketamine or lanicemine. (b) The genus levels of Clostridium were significantly altered (one-way ANOVA: F_3,20 = 55.538, P < 0.001). Data are shown as mean ± S.E.M. (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001.