Potentiation of antidepressant effects: NPY1R agonist and ketamine synergy enhances TrkB signaling and neurogenesis in the ventral hippocampus

ABSTRACT

Background

Major Depressive Disorder (MDD) poses a significant challenge to global health, with current treatments often limited by efficacy and onset delays. This study explores the synergistic antidepressant-like effects of an NPY1R agonist and Ketamine, targeting their neurobiological interactions within the ventral hippocampus.

Research Design and Methods

Utilizing a preclinical model, this study administered Neuropeptide Y receptor 1 (NPY1R) agonist and Ketamine, both separately and in combination, through intracerebroventricular (icv) and intranasal (i.n.) routes. The Forced Swimming Test (FST) was employed to assess antidepressant-like activity, while in situ Proximity Ligation Assay and immunohistochemistry were used to examine NPY1R/TrkB heteroreceptor complexes and BDNF expression in the ventral dentate gyrus (DG), along with neurogenesis markers.

Results

The combined treatment significantly reduced immobility in the FST, indicative of enhanced antidepressant-like effects, correlated with increased formation of NPY1R/TrkB complex and brain-derived neurotrophic factor (BDNF) expression in the ventral DG. These molecular alterations were associated with increased neurogenesis.

Conclusions

The coadministration of an NPY1R agonist and Ketamine in a rodent model demonstrated potentiated antidepressant responses through synergistic neurobiological pathways, including TrkB signaling and hippocampal neurogenesis. This indicates a novel therapeutic strategy for MDD, warranting further clinical investigation to fully understand its implications.

KEYWORDS:

• Antidepressant therapy
• Brain-Derived Neurotrophic Factor (BDNF)
• ketamine
• neurogenesis
• NPY1R agonist
• ventral hippocampus

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

C Arrabal-Gómez contributed significantly to the experimental execution, conception and design of the study. He also played a vital role in the drafting of the manuscript and provided critical revisions related to important intellectual content.

P Serrano-Castro was heavily involved in the analysis and interpretation of data, ensuring the accuracy and integrity of the work. He also contributed to the manuscript’s critical revisions and approved the final version for publication.

JA Sánchez-Pérez focused on data collection phases of the study, contributing to both the drafting and critical revision processes of the manuscript. He approved the final manuscript version.

N Garcia-Casares participated in the study’s design, particularly in the selection of methodological approaches for data analysis. She was also involved in drafting the manuscript and revising it critically for important intellectual content.

K Fuxe and D Borroto-Escuela played a key role in the conception and design of the study, especially in integrating the neurobiological and pharmacological aspects. They contributed to drafting the manuscript and critically revising it for significant intellectual content.

M Narváez was instrumental in the overall conception, design, and coordination of the study. He led the drafting of the manuscript and its critical revision for important intellectual content. As the corresponding author, he also took responsibility for the final approval of the version to be published and agreed to be accountable for all aspects of the work. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Availability of data and materials

The data that support the findings of this study are openly available in the Institutional repository of the University of Malaga (RIUMA) and from the corresponding author upon reasonable request.

Ethics approval and consent to participate

All experimental protocols were approved by the Local Animal Ethics, Care, and Use Committee for the University of Málaga, Spain (CEUMA 45–2022-A), and conducted in accordance with the EU Directive 2010/63/EU and Spanish Directive (Real Decretory 53/2013).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2024.2342524

Additional information

Funding

This manuscript was funded by the UMA18-FEDERJA-100 and ProyExcel_00613, Junta de Andalucía, Spain, to MN. Funding for open access charge: Universidad de Málaga/CBUA. Additional funding support came from Cátedra Imbrain: Neurociencia Integrada y Bionestar to MN. This work also received support from Stiftelsen Olle Engkvist Byggmästare in 2018 and 2021, as well as from the Swedish Medical Research Council (Grant No. 62X-00715-50-3) awarded to KF and DB-E. Additionally, funding was provided by Hjärnfonden (Grants F02018-0286 and F02019-0296), Karolinska Institutet Forskningsstiftelser 2022, EMERGIA 2020-39318 (Plan Andaluz de Investigación, Desarrollo e Innovación 2020), and CONSOLIDACION INVESTIGADORA (CNS2022-136008, Programa Estatal para Desarrollar, Atraer y Retener Talento, del Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023) awarded to DB-E. DB-E is affiliated with the Academia de Biólogos Cubanos and the Observatorio Cubano de Neurociencias (Yaguajay, Cuba).