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Augmentation effect of ketamine by guanosine in the novelty-suppressed feeding test is dependent on mTOR signaling pathway.

Abstract：

:The ketamine's potential for the treatment of refractory depression and anxiety has been considered one the most important discoveries in the last years, however, repeated use of ketamine is limited due to its side/adverse effects. Therefore, the search for effective augmentation strategies that may reduce ketamine doses is welcome. Therefore, this study sought to augment the effect of ketamine by guanosine in the novelty-suppressed feeding (NSF) test, a behavioral paradigm able to detect depression/anxiety-related behavior. Acute administration of guanosine (0.05 mg/kg, p.o.), similar to ketamine (1 mg/kg, i.p.), produced a rapid behavioral response in mice submitted to NSF test. Moreover, the coadministration of sub-effective doses of guanosine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.) was effective in mice submitted to NSF test. Subsequently, the intracellular mechanism underpinning the augmentation effect of ketamine by guanosine was investigated. Our results suggest that augmentation response of ketamine by guanosine in the NSF test probably involves the activation of mTOR signaling, since the treatment with rapamycin (0.2 nmol/site, i.c.v., a selective mTOR inhibitor) completely abolished this effect. This augmentation strategy also increased mTOR phosphorylation (Ser2448) in the hippocampus, reinforcing the role of mTOR in this augmentation response. However, no changes in the p70S6K, PSD-95, GluA1, and synapsin immunocontents were found in the hippocampus of ketamine plus guanosine-treated mice. Overall, results provide evidence that guanosine is able to augment the effect of ketamine in the NSF test via mTOR activation, a finding that might have therapeutic implications for the management of depression/anxiety.

journal_name

J Psychiatr Res

journal_title

Journal of psychiatric research

authors

Camargo A,Pazini FL,Rosa JM,Wolin IAV,Moretti M,Rosa PB,Neis VB,Rodrigues ALS

doi

10.1016/j.jpsychires.2019.05.017

subject

Has Abstract

pub_date

2019-08-01 00:00:00

pages

103-112

eissn

0022-3956

issn

1879-1379

pii

S0022-3956(19)30242-0

journal_volume

115

pub_type

杂志文章

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Augmentation effect of ketamine by guanosine in the novelty-suppressed feeding test is dependent on mTOR signaling pathway.