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Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression

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Abstract

Rationale

In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states.

Objective

The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior.

Methods

In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland.

Results

The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline.

Conclusion

The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.

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Acknowledgements

This work was supported by grants from CONICET (Consejo Nacional de Investigación Científica y Técnica), SECyT-UNC (Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba), and the Swedish Research Council (VR, Medicine). We thank Grupo Pilar—GEPSA for the donation of the animals’ pelleted food and GADOR S.A. for the donation of fluoxetine and venlafaxine.

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Authors and Affiliations

  1. Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina

    María Belén Poretti, Marta Fiol de Cuneo & Valeria Paola Carlini

  2. Department of Neuroscience, Functional Pharmacology, Uppsala University, BMC, Uppsala, SE 75124, Sweden

    Rahul S. Sawant, Mathias Rask-Andersen & Helgi B. Schiöth

  3. Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina

    Mariela F. Perez

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  1. María Belén Poretti
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  2. Rahul S. Sawant
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  3. Mathias Rask-Andersen
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  4. Marta Fiol de Cuneo
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  5. Helgi B. Schiöth
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  6. Mariela F. Perez
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  7. Valeria Paola Carlini
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Correspondence to Mariela F. Perez or Valeria Paola Carlini.

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Marta Fiol de Cuneo, Mariela F. Perez, and Valeria Paola Carlini are established investigators from CONICET

Mariela F. Perez and Valeria Paola Carlini are joint last authors

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Poretti, M.B., Sawant, R.S., Rask-Andersen, M. et al. Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression. Psychopharmacology 233, 1077–1086 (2016). https://doi.org/10.1007/s00213-015-4187-4

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