Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice

Nathalie Alvarez-Ricartes, Patricia Oliveros-Matus, Cristhian Mendoza, Nelson Perez-Urrutia, Florencia Echeverria, Alexandre Iarkov*, George E. Barreto, Valentina Echeverria

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24 h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed.

Original languageEnglish
Pages (from-to)7949-7960
Number of pages12
JournalMolecular Neurobiology
Volume55
Issue number10
DOIs
StatePublished - 2018

Bibliographical note

Funding Information:
This material is the result of work supported with resources and the use of facilities at the Bay Pines VA Healthcare System. The contents do not necessarily represent the views of the Department of Veterans Affairs or the US government. Also, we thank Dr. William Fray and Dr. Leha Hanson from the Alzheimer’s Research Center at Regions Hospital, HealthPartners Research Foundation for providing training and guidance with the implementation of the intranasal delivery of drugs to mice. VE is the inventor of the approved patent US 20100104504 (August 2017).

Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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