Guanosine boosts the fast, but not sustained, antidepressant-like and pro-synaptogenic effects of ketamine by stimulating mTORC1-driven signaling pathway.

A. Camargo; A. P. Dalmagro; Eslen Delanogare; D. B. Fraga; Ingrid A V Wolin; A. Zeni; P. Brocardo; A. Rodrigues

doi:10.1016/j.euroneuro.2021.12.010

Guanosine boosts the fast, but not sustained, antidepressant-like and pro-synaptogenic effects of ketamine by stimulating mTORC1-driven signaling pathway.

A. Camargo, A. P. Dalmagro, Eslen Delanogare, D. B. Fraga, Ingrid A V Wolin, A. Zeni, P. Brocardo, A. Rodrigues

European Neuropsychopharmacology January 7, 2022 DOI: 10.1016/j.euroneuro.2021.12.010 (opens in new tab)

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Study at a glance

AI-extracted from the abstract

Characteristics	Preclinical animal study Peer reviewed
Population	Mice
Interventions	Ketamine plus guanosine rapamycin
Dose	ketamine 0.1 mg/kg i.p.; guanosine 0.01 mg/kg p.o.; rapamycin 0.2 nmol/site i.c.v.
Duration	Up to 7 days
Topics	Esketamine Ketamine
Post-publication review	2 comments on PubPeer (opens in new tab) · last active January 2024
Key points	Guanosine potentiates the fast antidepressant-like and pro-synaptogenic effects of subthreshold ketamine in mice via an mTORC1-dependent mechanism, with effects lasting up to 24 hours but not 7 days.

Abstract

The mTORC1-dependent dendritic spines formation represents a key mechanism for fast and long-lasting antidepressant responses, but it remains to be determined whether this mechanism may account for the ability of guanosine in potentiating ketamine's actions. Here, we investigated the ability of ketamine plus guanosine to elicit fast and sustained antidepressant-like and pro-synaptogenic effects in mice and the role of mTORC1 signaling in these responses. The combined administration of subthreshold doses of ketamine (0.1 mg/kg, i.p.) and guanosine (0.01 mg/kg, p.o.) caused a fast (1 h - 24 h), but not long-lasting (7 days) reduction in the immobility time in the tail suspension test. This behavioral effect was paralleled by a rapid (started in 1 h) and transient (back to baseline in 24 h) increase on BDNF, p-Akt (Ser473), p-GSK-3β (Ser9), p-mTORC1 (Ser2448), p-p70S6K (Thr389) immunocontent in the hippocampus, but not in the prefrontal cortex. Conversely, ketamine plus guanosine increased PSD-95 and GluA1 immunocontent in the prefrontal cortex, but not the hippocampus after 1 h, whereas increased levels of these proteins in both brain structures were observed after 24 h, but these effects did not persist after 7 days. The combined administration of ketamine plus guanosine raised the dendritic spines density in the ventral hippocampal DG and prefrontal cortex after 24 h Rapamycin (0.2 nmol/site, i.c.v.) abrogated the antidepressant-like effect and pro-synaptogenic responses triggered by ketamine plus guanosine. These results indicate that guanosine may boost the antidepressant-like effect of ketamine for up to 24 h by a mTORC1-dependent mechanism.

Comparable studies

Other preclinical and animal studies on ketamine, most cited first.

Study	Year	Design
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats	2010	Observational study
Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats	1997	Dose-response study with microdialysis and behavioral testing
NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice	2016	Preclinical study
The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats	1983	Experimental study
R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice	2015	Experimental study

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