Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression
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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.
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.
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.
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.
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.
KeywordsVasopressin Corticotropin releasing hormone CRHR1 AVPr1b Fluoxetine Venlafaxine Depressive behavior
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.
Compliance with ethical standard
Conflict of interest
The authors declare that they have no competing interests.
- Anderson IM, Nutt DJ, Deakin JF, British Association for Psychopharmacology (2000) Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. Journal of psychopharmacology 14:3–20CrossRefPubMedGoogle Scholar
- Bank W (2004) The Global Burden of Disease. 2004 Update. Oxford University Press, OxfordGoogle Scholar
- Barden N (2004) Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. Journal of psychiatry & neuroscience : JPN 29:185–193Google Scholar
- Brady LS, Whitfield HJ Jr, Fox RJ, Gold PW, Herkenham M (1991) Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. The Journal of clinical investigation 87:831–837PubMedCentralCrossRefPubMedGoogle Scholar
- Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates: compact 3rd. Accademic Press, New York, USAGoogle Scholar
- Griebel G, Simiand J, Serradei Le Gal C, Wagnon J, Pascal M, Scatton B, Maffrand JP, Soubrie P (2002a) Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders. Proceedings of the National Academy of Sciences of the United States of America 99:6370–6375PubMedCentralCrossRefPubMedGoogle Scholar
- Griebel G, Simiand J, Steinberg R, Jung M, Gully D, Roger P, Geslin M, Scatton B, Maffrand JP, Soubrie P (2002b) 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylp henyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders. The Journal of pharmacology and experimental therapeutics 301:333–345CrossRefPubMedGoogle Scholar
- Grigoriadis DE, Pearsall D, De Souza EB (1989) Effects of chronic antidepressant and benzodiazepine treatment on corticotropin-releasing-factor receptors in rat brain and pituitary. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2:53–60CrossRefGoogle Scholar
- Liu ZC, Luo XN, Wang GH (2002) Corticotropin-releasing factor and major depression. Foreign Medical Sci (Section of Psychiatry) 2:156–158Google Scholar
- Machado DG, Kaster MP, Binfare RW, Dias M, Santos AR, Pizzolatti MG, Brighente IM, Rodrigues AL (2007) Antidepressant-like effect of the extract from leaves of Schinus molle L. in mice: evidence for the involvement of the monoaminergic system. Progress in neuro-psychopharmacology & biological psychiatry 31:421–428CrossRefGoogle Scholar
- Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO, Anisman H (2004) Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. The Journal of neuroscience : the official journal of the Society for Neuroscience 24:1478–1485CrossRefGoogle Scholar
- Okuyama S, Chaki S, Kawashima N, Suzuki Y, Ogawa S, Nakazato A, Kumagai T, Okubo T, Tomisawa K (1999) Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001. The Journal of pharmacology and experimental therapeutics 289:926–935PubMedGoogle Scholar
- Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. The American journal of psychiatry 163:1905–1917CrossRefPubMedGoogle Scholar
- Teter CJ, Kando JC, Wells BG (2008) Major depressive disorder. In: DiPiro RLTJT, Yee GC, Matke GR, Wells BG, Posey LM (eds) Pharmacotherapy: A Pathophysiologic Approach. The McGraw-Hill Companies, Inc., Columbus, OH, USAGoogle Scholar