, Volume 233, Issue 6, pp 1077–1086 | Cite as

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

  • María Belén Poretti
  • Rahul S. Sawant
  • Mathias Rask-Andersen
  • Marta Fiol de Cuneo
  • Helgi B. Schiöth
  • Mariela F. PerezEmail author
  • Valeria Paola CarliniEmail author
Original Investigation



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.


Vasopressin 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.

Supplementary material

213_2015_4187_MOESM1_ESM.docx (104 kb)
ESM 1 (DOCX 103 kb)


  1. Aguilera G, Rabadan Diehl C (2000) Regulation of vasopressin V1b receptors in the anterior pituitary gland of the rat. Exp Physiol 85:19S–26S, Spec No CrossRefPubMedGoogle Scholar
  2. Ahrens T, Deuschle M, Krumm B, Van Der Pompe G, Den Boer JA, Lederbogen F (2008) Pituitary-adrenal and sympathetic nervous system responses to stress in women remitted from recurrent major depression. Psychosom Med 70:461–467CrossRefPubMedGoogle Scholar
  3. 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
  4. Antoni FA (1993) Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age. Frontiers in neuroendocrinology 14:76–122CrossRefPubMedGoogle Scholar
  5. Bank W (2004) The Global Burden of Disease. 2004 Update. Oxford University Press, OxfordGoogle Scholar
  6. Barden N (2004) Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. Journal of psychiatry & neuroscience : JPN 29:185–193Google Scholar
  7. Binfare RW, Rosa AO, Lobato KR, Santos AR, Rodrigues AL (2009) Ascorbic acid administration produces an antidepressant-like effect: evidence for the involvement of monoaminergic neurotransmission. Progress in neuro-psychopharmacology & biological psychiatry 33:530–540CrossRefGoogle Scholar
  8. Brady LS, Gold PW, Herkenham M, Lynn AB, Whitfield HJ Jr (1992) The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. Brain research 572:117–125CrossRefPubMedGoogle Scholar
  9. 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
  10. Brocardo PS, Budni J, Kaster MP, Santos AR, Rodrigues AL (2008) Folic acid administration produces an antidepressant-like effect in mice: evidence for the involvement of the serotonergic and noradrenergic systems. Neuropharmacology 54:464–473CrossRefPubMedGoogle Scholar
  11. Cairncross KD, Cox B, Forster C, Wren AF (1979) Olfactory projection systems, drugs and behaviour: a review. Psychoneuroendocrinology 4:253–272CrossRefPubMedGoogle Scholar
  12. Carpenter LL, Ross NS, Tyrka AR, Anderson GM, Kelly M, Price LH (2009) Dex/CRH test cortisol response in outpatients with major depression and matched healthy controls. Psychoneuroendocrinology 34:1208–1213PubMedCentralCrossRefPubMedGoogle Scholar
  13. Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790CrossRefPubMedGoogle Scholar
  14. Chaki S, Nakazato A, Kennis L, Nakamura M, Mackie C, Sugiura M, Vinken P, Ashton D, Langlois X, Steckler T (2004) Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450. European journal of pharmacology 485:145–158CrossRefPubMedGoogle Scholar
  15. De Oliveira RA, Cunha GM, Borges KD, De Bruin GS, Dos Santos Filho EA, Viana GS, De Bruin VM (2004) The effect of venlafaxine on behaviour, body weight and striatal monoamine levels on sleep-deprived female rats. Pharmacology, biochemistry, and behavior 79:499–506CrossRefPubMedGoogle Scholar
  16. Dhir A, Kulkarni SK (2008) Venlafaxine reverses chronic fatigue-induced behavioral, biochemical and neurochemical alterations in mice. Pharmacology, biochemistry, and behavior 89:563–571CrossRefPubMedGoogle Scholar
  17. Ellingrod VL, Perry PJ (1994) Venlafaxine: a heterocyclic antidepressant. Am J Hosp Pharm 51:3033–3046PubMedGoogle Scholar
  18. Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates: compact 3rd. Accademic Press, New York, USAGoogle Scholar
  19. Frazer A (1997) Pharmacology of antidepressants. J Clin Psychopharmacol 17(Suppl 1):2S–18SCrossRefPubMedGoogle Scholar
  20. Frisch P, Bilkei-Gorzo A, Racz I, Zimmer A (2010) Modulation of the CRH system by substance P/NKA in an animal model of depression. Behav Brain Res 213:103–108CrossRefPubMedGoogle Scholar
  21. Gillies GE, Linton EA, Lowry PJ (1982) Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 299:355–357CrossRefPubMedGoogle Scholar
  22. 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
  23. 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
  24. 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
  25. Heilig M, Ekman R (1995) Chronic parenteral antidepressant treatment in rats: unaltered levels and processing of neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH). Neurochemistry international 26:351–355CrossRefPubMedGoogle Scholar
  26. Holsboer F, Barden N (1996) Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocrine reviews 17:187–205CrossRefPubMedGoogle Scholar
  27. Jancsar SM, Leonard BE (1984) The effect of (+/−)mianserin and its enantiomers on the behavioural hyperactivity of the olfactory-bulbectomized rat. Neuropharmacology 23:1065–1070CrossRefPubMedGoogle Scholar
  28. Jesberger JA, Richardson JS (1988) Brain output dysregulation induced by olfactory bulbectomy: an approximation in the rat of major depressive disorder in humans? Int J Neurosci 38:241–265CrossRefPubMedGoogle Scholar
  29. Kelly JP, Wrynn AS, Leonard BE (1997) The olfactory bulbectomized rat as a model of depression: an update. Pharmacol Ther 74:299–316CrossRefPubMedGoogle Scholar
  30. Kokras N, Sotiropoulos I, Pitychoutis PM, Almeida OF, Papadopoulou-Daifoti Z (2011) Citalopram-mediated anxiolysis and differing neurobiological responses in both sexes of a genetic model of depression. Neuroscience 194:62–71CrossRefPubMedGoogle Scholar
  31. Liu ZC, Luo XN, Wang GH (2002) Corticotropin-releasing factor and major depression. Foreign Medical Sci (Section of Psychiatry) 2:156–158Google Scholar
  32. 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
  33. Mar A, Spreekmeester E, Rochford J (2002) Fluoxetine-induced increases in open-field habituation in the olfactory bulbectomized rat depend on test aversiveness but not on anxiety. Pharmacology, biochemistry, and behavior 73:703–712CrossRefPubMedGoogle Scholar
  34. Marar IE, Amico JA (1998) Vasopressin, oxytocin, corticotrophin-releasing factor, and sodium responses during fluoxetine administration in the rat. Endocrine 8:13–18CrossRefPubMedGoogle Scholar
  35. Marcilhac A, Anglade G, Hery F, Siaud P (1999) Olfactory bulbectomy increases vasopressin, but not corticotropin-releasing hormone, content in the external layer of the median eminence of male rats. Neuroscience letters 262:89–92CrossRefPubMedGoogle Scholar
  36. 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
  37. Murray CJ, Lopez AD (1997) Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 349:1498–1504CrossRefPubMedGoogle Scholar
  38. Nemeroff CB, Owens MJ (2004) Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis. CNS Spectr 9:23–31PubMedGoogle Scholar
  39. Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M (1988) Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Archives of general psychiatry 45:577–579CrossRefPubMedGoogle Scholar
  40. Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen PT, Vale W (1984) Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226:1342–1344CrossRefPubMedGoogle Scholar
  41. Noguchi S, Inukai T, Kuno T, Tanaka C (1992) The suppression of olfactory bulbectomy-induced muricide by antidepressants and antihistamines via histamine H1 receptor blocking. Physiology & behavior 51:1123–1127CrossRefGoogle Scholar
  42. 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
  43. Poretti MB, Rask-Andersen M, Kumar P, Rubiales de Barioglio S, Fiol de Cuneo M, Schioth HB, Carlini VP (2015) Ghrelin effects expression of several genes associated with depression-like behavior. Progress in neuro-psychopharmacology & biological psychiatry 56:227–234CrossRefGoogle Scholar
  44. Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF (1994) Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60:436–444CrossRefPubMedGoogle Scholar
  45. Rabadan-Diehl C, Lolait SJ, Aguilera G (1995) Regulation of pituitary vasopressin V1b receptor mRNA during stress in the rat. Journal of neuroendocrinology 7:903–910CrossRefPubMedGoogle Scholar
  46. Redrobe JP, Bourin M, Colombel MC, Baker GB (1998) Dose-dependent noradrenergic and serotonergic properties of venlafaxine in animal models indicative of antidepressant activity. Psychopharmacology 138:1–8CrossRefPubMedGoogle Scholar
  47. Richardson JS (1991) Animal models of depression reflect changing views on the essence and etiology of depressive disorders in humans. Progress in neuro-psychopharmacology & biological psychiatry 15:199–204CrossRefGoogle Scholar
  48. Rivier C, Rivier J, Mormede P, Vale W (1984) Studies of the nature of the interaction between vasopressin and corticotropin-releasing factor on adrenocorticotropin release in the rat. Endocrinology 115:882–886CrossRefPubMedGoogle Scholar
  49. 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
  50. Scott LV, Dinan TG (1998) Vasopressin and the regulation of hypothalamic-pituitary-adrenal axis function: implications for the pathophysiology of depression. Life sciences 62:1985–1998CrossRefPubMedGoogle Scholar
  51. Shibata S, Watanabe S, Liou SY, Ueki S (1983) Effects of adrenergic blockers on the inhibition of muricide by desipramine and noradrenaline injected into the amygdala in olfactory bulbectomized rats. Pharmacology, biochemistry, and behavior 18:203–207CrossRefPubMedGoogle Scholar
  52. Song C, Leonard BE (2005) The olfactory bulbectomised rat as a model of depression. Neuroscience and biobehavioral reviews 29:627–647CrossRefPubMedGoogle Scholar
  53. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370CrossRefPubMedGoogle Scholar
  54. Stewart LQ, Roper JA, Young WS 3rd, O’Carroll AM, Lolait SJ (2008) Pituitary-adrenal response to acute and repeated mild restraint, forced swim and change in environment stress in arginine vasopressin receptor 1b knockout mice. Journal of neuroendocrinology 20:597–605CrossRefPubMedGoogle Scholar
  55. Stout SC, Owens MJ, Nemeroff CB (2002) Regulation of corticotropin-releasing factor neuronal systems and hypothalamic-pituitary-adrenal axis activity by stress and chronic antidepressant treatment. The Journal of pharmacology and experimental therapeutics 300:1085–1092CrossRefPubMedGoogle Scholar
  56. Swiergiel AH, Leskov IL, Dunn AJ (2008) Effects of chronic and acute stressors and CRF on depression-like behavior in mice. Behav Brain Res 186:32–40CrossRefPubMedGoogle Scholar
  57. 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
  58. Tizabi Y, Skofitsch G, Jacobowitz DM (1985) Effect of chronic reserpine and desmethylimipramine treatment on CRF-like immunoreactivity of discrete brain areas of rat. Brain research 335:389–391CrossRefPubMedGoogle Scholar
  59. Uriguen L, Arteta D, Diez-Alarcia R, Ferrer-Alcon M, Diaz A, Pazos A, Meana JJ (2008) Gene expression patterns in brain cortex of three different animal models of depression. Genes Brain Behav 7:649–658CrossRefPubMedGoogle Scholar
  60. Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, Vale W, Sawchenko PE (2000) Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 428:191–212CrossRefPubMedGoogle Scholar
  61. Weingartner H, Silberman E (1982) Models of cognitive impairment: cognitive changes in depression. Psychopharmacology bulletin 18:27–42PubMedGoogle Scholar
  62. Wong ML, Licinio J (2001) Research and treatment approaches to depression. Nature reviews Neuroscience 2:343–351CrossRefPubMedGoogle Scholar
  63. Yang J, Pan YJ, Yin ZK, Hai GF, Lu L, Zhao Y, Wang DX, Wang H, Wang G (2012) Effect of arginine vasopressin on the behavioral activity in the behavior despair depression rat model. Neuropeptides 46:141–149CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • María Belén Poretti
    • 1
  • Rahul S. Sawant
    • 2
  • Mathias Rask-Andersen
    • 2
  • Marta Fiol de Cuneo
    • 1
  • Helgi B. Schiöth
    • 2
  • Mariela F. Perez
    • 3
    Email author
  • Valeria Paola Carlini
    • 1
    Email author
  1. 1.Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias MédicasCONICET and Universidad Nacional de CórdobaCórdobaArgentina
  2. 2.Department of Neuroscience, Functional PharmacologyUppsala University, BMCUppsalaSweden
  3. 3.Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Facultad de Ciencias QuímicasUniversidad Nacional de CórdobaCórdobaArgentina

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