Guanosine potentiates the antidepressant-like effect of subthreshold doses of ketamine: Possible role of pro-synaptogenic signaling pathway

Abstract

Background Augmentation therapies may be effective strategies to potentiate the ketamine's actions with lower potential for knock-on effects. Thus, this study investigated the ability of combined administration of guanosine plus ketamine to elicit an antidepressant-like effect associated with mTOR pathway modulation. The ability of this combined administration to exert an antidepressant-like effect in a model of depression was also evaluated.Methods Mice were administered with subthreshold doses of ketamine (0.1 mg/kg, i.p.) and guanosine (0.01 mg/kg, p.o.) and submitted to the tail suspension test, and immunoblotting analyses (p-mTOR, p-p70S6K, PSD-95, GluA1, and synapsin) in the hippocampus and prefrontal cortex. The antidepressant-like effect of ketamine plus guanosine in mice subjected to administration of corticosterone (20 mg/kg, p.o., 21 days) was also evaluated.Results Ketamine plus guanosine treatment elicited an antidepressant-like effect, which was associated with increased mTOR (Ser2448) and p70S6K (Thr389) phosphorylation in the hippocampus, but not in the prefrontal cortex. Furthermore, increased PSD-95 and GluA1 immunocontent were observed in the prefrontal cortex, but not in the hippocampus of ketamine plus guanosine-treated mice. Reinforcing the notion that guanosine may potentiate the ketamine's behavioral response, a single administration of subthreshold doses of ketamine plus guanosine counteracted the corticosterone-induced depressive-like behavior.Conclusions Our results indicate that guanosine potentiates the antidepressant-like effect of subthreshold doses of ketamine, an effect likely associated with the stimulation of synaptogenic pathway in the hippocampus and prefrontal cortex, although with a different profile. The augmentation effect of ketamine by guanosine could have therapeutic relevance for patients with treatment-resistant depression.