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

Combining low doses of ketamine and guanosine produces an antidepressant-like effect in mice, likely by activating synaptogenic signaling pathways in the hippocampus and prefrontal cortex. The treatment increased phosphorylation of mTOR and p70S6K in the hippocampus and raised levels of synaptic proteins PSD-95 and GluA1 in the prefrontal cortex. A single co-administration also reversed depressive-like behavior induced by chronic corticosterone exposure. The authors suggest that guanosine could augment ketamine's effects, potentially offering a therapeutic strategy for treatment-resistant depression.

Study at a glance

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.