56. Ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57Bl/6J mice by increasing AMPA receptor-mediated glutamatergic neurotransmission over NMDA receptor-mediated neurotransmission

We have demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO), which degrades tryptophan along the kynurenine pathway. Using LC-MS analysis of kynurenine metabolites in the brain and plasma of mice injected with LPS (1 mg/kg, intraperitoneally), we demonstrate that LPS selectively activates the kynunrenine monooxygenase pathway that results in the production of the N-methyl- d -aspartate (NMDA) receptor agonist quinolinic acid. We also show that administration of the NMDA receptor antagonist ketamine (6 mg/kg, intraperitoneally) immediately prior to LPS (0.83 mg/kg, intraperitoneally) in C57Bl/6J mice abrogates the onset of LPS-induced depressive-like behavior in the forced swim and sucrose preference tests but fails to influence LPS-induced sickness. Ketamine did not affect hepatic and brain LPS-induced cytokine expression, IDO activation, and brain-derived neurotrophic factor (BDNF) transcripts. The antidepressant-like effect of ketamine independent of any effect on LPS-induced sickness was confirmed when ketamine was administered 10 h after LPS instead of immediately beforehand. Ketamine had no effect when administered 24 h prior to LPS. Confirmation of ketamine’s ability to abrogate LPS-induced depressive-like behavior by antagonizing the NMDA receptor and enhancing AMPA-mediated glutamatergic neurotransmission was obtained by pretreating mice with the AMPA receptor antagonist NBQX (10 mg/kg intraperitoneally). NBQX pretreatment restored LPS-induced decreased sucrose preference. These findings suggest that LPS-induced depressive-like behavior is mediated by NMDA receptor activation as a consequence of formation of quinolinic acid.