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Venlafaxine’s effect on resilience to stress is associated with a shift in the balance between glucose and fatty acid utilization

Neuropsychopharmacology volume 48, pages 1475–1483 (2023)Cite this article

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Abstract

Brain metabolism is a fundamental process involved in the proper development of the central nervous system and in the maintenance of the main higher functions in humans. As consequence, energy metabolism imbalance has been commonly associated to several mental disorders, including depression. Here, by employing a metabolomic approach, we aimed to establish if differences in energy metabolite concentration may underlie the vulnerability and resilience in an animal model of mood disorder named chronic mild stress (CMS) paradigm. In addition, we have investigated the possibility that modulation of metabolite concentration may represent a pharmacological target for depression by testing whether repeated treatment with the antidepressant venlafaxine may normalize the pathological phenotype by acting at metabolic level. The analyses were conducted in the ventral hippocampus (vHip) for its key role in the modulation of anhedonia, a core symptom of patients affected by depression. Interestingly, we showed that a shift from glycolysis to beta oxidation seems to be responsible for the vulnerability to chronic stress and that vHip metabolism contributes to the ability of the antidepressant venlafaxine to normalize the pathological phenotype, as shown by the reversal of the changes observed in specific metabolites. These findings may provide novel perspectives on metabolic changes that could serve as diagnostic markers and preventive strategies for the early detection and treatment of depression as well as for the identification of potential drug targets.

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Fig. 1: Schematic representation of the experimental paradigms.
Fig. 2: Behavioral characterization of rats exposed to 6 weeks of chronic mild stress (CMS).
Fig. 3: Metabolite levels in the vHip of rats vulnerable and resilient to 6 weeks of chronic mild stress.
Fig. 4: Behavioral characterization of rats exposed to 6 weeks of chronic mild stress (CMS) and treated with venlafaxine (VLX) for 3 weeks.
Fig. 5: Metabolite levels in vHip modulated by chronic mild stress and normalized by venlafaxine (VLX) administration.

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Funding

Funding

The behavioral part of the study was supported by the statutory activity of the Maj Institute of Pharmacology Polish Academy of Sciences (Krakow, Poland). The molecular study was supported by Ministero dell’Istruzione, dell’Università e della Ricerca to FC (PRIN2017, Project number 2017MLC3NF), by the Ministry of University and Research (MUR) Progetto Eccellenza (2023–2027) to the Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano and partially by the Italian Ministry of Health with Ricerca Corrente and 5×1000 funds to NM Maria Teresa Gallo was supported by cycle XXXVII of the doctorate in Pharmacological Biomolecular Sciences, Experimental and Clinical, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano.

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Authors and Affiliations

  1. Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Milan, Italy

    Paola Brivio, Matteo Audano, Maria Teresa Gallo, Eleonora Miceli, Fabio Fumagalli, Nico Mitro & Francesca Calabrese

  2. Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland

    Piotr Gruca, Magdalena Lason, Ewa Litwa & Mariusz Papp

  3. Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Nico Mitro

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  1. Paola Brivio
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  2. Matteo Audano
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  3. Maria Teresa Gallo
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  11. Francesca Calabrese
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Contributions

PB: conceptualization, formal analysis, data curation, investigation, writing original draft. MA: methodology, formal analysis. MTG: formal analysis. EM: formal analysis. PG: methodology. ML: methodology. EL: methodology. FF: review and editing. MP: methodology, review and editing. NM: data curation, review and editing. FC: conceptualization, visualization, writing original draft.

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Correspondence to Francesca Calabrese.

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Brivio, P., Audano, M., Gallo, M.T. et al. Venlafaxine’s effect on resilience to stress is associated with a shift in the balance between glucose and fatty acid utilization. Neuropsychopharmacol. 48, 1475–1483 (2023). https://doi.org/10.1038/s41386-023-01633-0

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