NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice

Abstract

We have previously demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO; O'Connor et al, 2009c). IDO degrades tryptophan along the kynurenine pathway. Using mass-spectrometry (LC-MS) analysis of kynurenine metabolites in the brain of mice injected at the periphery with 1 mg/kg LPS, we show that LPS activates the kynurenine 3-monooxygenase pathway that ultimately degrades kynurenine into quinolinic acid. As quinolinic acid acts as an N-methyl-D-aspartate (NMDA) receptor agonist, we used the NMDA receptor antagonist ketamine to assess the role of NMDA receptor activation in LPS-induced depressive-like behavior. Here, we report that a low dose of ketamine (6 mg/kg, intraperitoneally) immediately before administration of LPS (0.83 mg/kg, intraperitoneally) in C57Bl/6 J mice abrogated the development of LPS-induced depressive-like behavior, without altering LPS-induced sickness measured by body weight loss, decreased motor activity, and reduced food intake. Depressive-like behavior was measured 24 h after LPS by decreased sucrose preference and increased immobility in the forced swim test (FST). Ketamine had no effect on LPS-induced cytokine expression in the liver and brain, IDO activation, and brain-derived neurotrophic factor (BDNF) transcripts. The ability of ketamine to abrogate LPS-induced depressive-like behavior independently of a possible interference with LPS-induced inflammatory signaling was confirmed when ketamine was administered 10 h after LPS instead of immediately before LPS. In contrast, ketamine had no effect when administered 24 h before LPS. To confirm that NMDA receptor antagonism by ketamine mediates the antidepressant-like activity of this compound in LPS-treated mice, mice were pretreated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX) to block enhanced AMPA receptor glutamatergic neurotransmission after NMDA receptor antagonism by ketamine. NBQX administered at the dose of 10 mg/kg intraperitoneally 15 min before ketamine in mice treated with LPS 24 h earlier restored LPS-induced decreased sucrose preference. These findings indicate that LPS-induced depressive-like behavior is mediated by NMDA receptor activation, probably as a consequence of formation of quinolinic acid.

Figure 1

Experimental timeline and design. BW, body weight; LMA, locomotor activity; FST, forced swim test; LPS, lipopolysaccharide; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione.

Figure 2

Ketamine abrogates lipopolysaccharide (LPS)-induced depressive-like behavior. (a) Mean sucrose preference (%) (±SEM) for mice treated with ketamine or phosphate-buffered saline (PBS) immediately before LPS or PBS treatment (n⩾7 per group). (b) Mean time spent immobile in the forced swim test (s) (±SEM) for mice treated with ketamine or PBS immediately before LPS or PBS treatment (n=8 per group). Filled bars represent ketamine-treated mice that were treated with either LPS or PBS, and hollow bars represent PBS controls that were treated with either LPS or PBS. *p<0.05.

Figure 3

Ketamine treatment 10 h after administration of lipopolysaccharide (LPS) but not 24 h before abrogates LPS-induced depressive-like behavior. (a and b) Mean sucrose preference (%) (±SEM) and time spent immobile in the forced swim test (s) (±SEM) for mice treated with ketamine or phosphate-buffered saline (PBS) 24 h before LPS or PBS treatment (n⩾6 for all groups). (c) Mean sucrose preference (%) (±SEM) for mice treated with ketamine or PBS 10 h after LPS or PBS treatment (n⩾6 for all groups). Filled bars represent ketamine-treated mice that were treated with either LPS or PBS, and hollow bars represent PBS controls that were treated with either LPS or PBS. *p<0.05.

Figure 4

NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione) restores reduced sucrose preference in lipopolysaccharide (LPS)-treated mice administered ketamine. Mean sucrose preference (%) (±SEM) for LPS-treated mice treated with ketamine or phosphate-buffered saline (PBS) 15 min after NBQX or control treatment (n⩾6 per group). Filled bars represent NBQX-treated mice that were treated with either ketamine or PBS, and hollow bars represent controls that were treated with either ketamine or PBS. *p<0.05.