Ketamine, but not guanosine, as a prophylactic agent against corticosterone-induced depressive-like behavior: Possible role of long-lasting pro-synaptogenic signaling pathway
A. Camargo, A. P. Dalmagro, M. M. de Souza, A. Zeni, A. L. S. Rodrigues
Experimental Neurology September 3, 2020 DOI: 10.1016/j.expneurol.2020.113459 (opens in new tab) via Semantic Scholar
Summary
AI-generated from the abstractA single injection of ketamine given a week before stress prevented depressive-like behavior in mice, while guanosine did not. The stressor, corticosterone, reduced proteins linked to synapse health in the hippocampus, and ketamine blocked that reduction. Combining low doses of ketamine and guanosine partly prevented one measure of depressive-like behavior. Fluoxetine given for three weeks did not prevent the stress effects. The findings suggest ketamine's lasting protective effect against depression involves pro-synaptogenic signaling in the hippocampus.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine Guanosine Fluoxetine |
| Dose | 5 mg/kg, i.p. (ketamine); 1 or 5 mg/kg, p.o. (guanosine); 1 mg/kg, i.p. (subthreshold ketamine); 5 mg/kg, p.o. (subthreshold guanosine) |
| Duration | Single administration one week before stress; fluoxetine for 3 weeks |
| Keywords | Medicine Psychology |
| Key finding | A single dose of ketamine, but not guanosine, given one week before corticosterone exposure prevented depressive-like behavior in mice, and this effect was associated with preventing reductions in hippocampal synaptic proteins. |
Abstract
Ketamine has been reported to exert a prophylactic effect against stress-induced depressive-like behavior by modulating the guanosine-based purinergic system. However, the molecular pathways underlying its prophylactic effect and whether guanosine also elicits a similar effect remain to be determined. Here, we investigated the prophylactic effect of ketamine and guanosine against corticosterone (CORT – 20 mg/kg, p.o.)-induced depressive-like behavior in mice. Furthermore, we characterized if the prophylactic response may be associated with mTORC1-driven signaling in the hippocampus and prefrontal cortex. A single administration of ketamine (5 mg/kg, i.p.), but not guanosine (1 or 5 mg/kg, p.o.), given 1 week before the pharmacological stress prevented CORT-induced depressive-like behavior in the tail suspension test (TST) and splash test (SPT). Fluoxetine treatment for 3 weeks did not prevent CORT-induced behavioral effects. A single administration of subthreshold doses of ketamine (1 mg/kg, i.p.) plus guanosine (5 mg/kg, p.o.) partially prevented the CORT-induced depressive-like behavior in the SPT. Additionally, CORT reduced Akt (Ser473) and GSK-3β (Ser9) phosphorylation and PSD-95, GluA1, and synapsin immunocontent in the hippocampus, but not in the prefrontal cortex. No alterations on mTORC1/p70S6K immunocontent were found in both regions in any experimental group. CORT-induced reductions on PSD-95, GluA1, and synapsin immunocontent were prevented only by ketamine treatment. Collectively, these findings suggest that ketamine, but not guanosine, exerts a prophylactic effect against depressive-like behavior, an effect associated with the stimulation of long-lasting pro-synaptogenic signaling in the hippocampus.