Journal
JOURNAL OF AFFECTIVE DISORDERS
Volume 271, Issue -, Pages 100-108Publisher
ELSEVIER
DOI: 10.1016/j.jad.2020.03.186
Keywords
Augmentation strategy; Depression; Corticosterone; Guanosine; Ketamine; mTOR
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Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [449436/2014-4, 310113/2017-2]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- CNPq Research Productivity Fellowship
- Laboratorio Multiusuario de Estudos em Biologia (LAMEB)
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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 (Ser(2448)) and p70S6K (Thr(389)) 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.
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