Ketamine modulates hippocampal neurogenesis and pro-inflammatory cytokines but not stressor induced neurochemical changes

• Published in: Neuropharmacology Vol. 112; no. Pt A; pp. 210 - 220
• Main Authors: Clarke, Melanie, Razmjou, Sara, Prowse, Natalie, Dwyer, Zach, Litteljohn, Darcy, Pentz, Rowan, Anisman, Hymie, Hayley, Shawn
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2017
• Subjects: Animals; Antidepressive Agents - administration & dosage; Biogenic Monoamines - metabolism; Corticosterone - blood; Cytokine; Cytokines - metabolism; Depression; Encephalitis - chemically induced; Encephalitis - complications; Encephalitis - metabolism; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiology; Illness Behavior; Interleukin-1beta - metabolism; Ketamine; Ketamine - administration & dosage; Lipopolysaccharides; LPS; Male; Mice; Neurogenesis; Neurogenesis - drug effects; Norepinephrine - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Restraint, Physical; Serotonin - metabolism; Stress, Psychological - chemically induced; Stress, Psychological - complications; Stress, Psychological - metabolism; Stressor; Tumor Necrosis Factor-alpha - metabolism; PBS; IL; FST; Cytokine; Depression; i.p; PFC; Neurogenesis; LPS; IFN; Ketamine; TNF-α; Stressor; 5-HIAA; ANOVA; GM-CSF; MHPG; NE; DCX; HPA; mTOR; NMDA; 5-HT; HPLC
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.04.021

Considerable recent attention has focused on the rapid antidepressant effects observed in treatment resistant patients produced by the NMDA receptor antagonist, ketamine. Surprisingly, the effects of ketamine in the context of stressor exposure, as well as the consequences of its chronic use are unclear. Thus, we assessed the impact of acute and repeated ketamine treatment together with acute [restraint or lipopolysaccharide (LPS)] or chronic (unpredictable different psychogenic challenges) stressor exposure. Importantly, acute ketamine treatment did provoke an antidepressant-like effect in a forced swim test (FST) and this effect lasted for 8 days following repeated exposure to the drug. Although acute restraint and LPS individually provoked the expected elevation of plasma corticosterone and brain-region specific monoamine variations, ketamine had no influence on corticosterone and had, at best, sparse effects on the monoamine changes. Similarly, ketamine did not appreciably influence the stressor induced neurochemical and sucrose preference alterations, it did however, dose-dependently reverse the LPS induced elevation of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Likewise, repeated ketamine administration increased adult hippocampal neurogenesis. These data indicate that repeated ketamine administration had greater behavioral consequences than acute treatment and that the drug might be imparting antidepressant effects through its effects on neuroplasticity and inflammatory processes rather than the typical neurochemical/hormonal factors affected by stressors. This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’. •Effects of acute and repeated ketamine treatment in stress-exposed mice were examined.•Repeated ketamine treatment prolonged antidepressant-like effects in a forced swim test.•Ketamine did not alter stress-induced corticosterone or monoamine changes.•Repeated ketamine treatment increased neurogenesis in the dentate gyrus of the hippocampus.•Acute ketamine treatment reversed pro-inflammatory cytokine production.