Skip to main content
SpringerLink
Log in

Effects of milnacipran and fluvoxamine on hyperemotional behaviors and the loss of tryptophan hydroxylase-positive cells in olfactory bulbectomized rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

It has been reported that many of the behavioral and serotonergic neuronal changes observed in olfactory bulbectomy (OBX) were improved by subchronic administration of a variety of antidepressants.

Objective

We examined the effects of subchronic treatment with milnacipran, a dual serotonin and noradrenaline reuptake inhibitors (SNRIs) and fluvoxamine, selective serotonin reuptake inhibitors (SSRI) in the OBX-induced hyperemotional behaviors and tryptophan hydroxylase (TPH), rate-limiting enzyme of 5-HT.

Materials and methods

The olfactory bulbs were removed by suction. Drugs were administered p.o. once daily for 8 days beginning 14 days post-surgery. The hyperemotionality behaviors of OBX rats were measured by rating scale and in the elevated plus-maze test.

Results

OBX rats, after milnacipran or fluvoxamine treatment, showed significant decrease in the score of hyperemotional responses on 7th day as compared with vehicle-treated OBX rats. In addition, milnacipran and fluvoxamine in OBX rats respectively produced a significant increase in the percentage of time spent in and number of entries into open arms in the elevated plus maze test. Furthermore, when 5-HTnergic neuronal function was examined using antibodies against tryptophan hydroxylase (TPH) following the behavioral tests, fluvoxamine significantly reversed the loss of TPH-positive cells produced by OBX in the dorsal raphe.

Conclusion

We demonstrated that chronic treatment with milnacipran or fluvoxamine was effective to improve both the hyperemotional behavior and the loss of TPH-positive cells seen in OBX rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Blier P, de Montigny C, Chaput Y (1990) A role for the serotonin system in the mechanism of action of antidepressant treatments: preclinical evidence. J Clin Psychiatry 51(Suppl):14–20

    PubMed  Google Scholar 

  • Bohmaker K, Bordi F, Meller E (1992) The effects of pertussis toxin on dopamine D2 and serotonin 5-HT1A autoreceptor-mediated inhibition of neurotransmitter synthesis: relationship to receptor reserve. Neuropharmacology 31:451–459

    Article  PubMed  CAS  Google Scholar 

  • Brady JV, Nauta WJ (1955) Subcortical mechanisms in emotional behavior: the duration of affective changes following septal and habenular lesions in the albino rat. J Comp Physiol Psychol 48:412–420

    Article  PubMed  CAS  Google Scholar 

  • 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. Eur J Pharmacol 485:145–158

    Article  PubMed  CAS  Google Scholar 

  • Esteban S, Llado J, Sastre-Coll A, Garcia-Sevilla JA (1999) Activation and desensitization by cyclic antidepressant drugs of alpha2-autoreceptors, alpha2-heteroreceptors and 5-HT1A-autoreceptors regulating monamine synthesis in the rat brain in vivo. Naunyn Schmiedebergs Arch Pharmacol 360:135–143

    Article  PubMed  CAS  Google Scholar 

  • Fukuchi T, Kanemoto K (2000) Differential effects of milnacipran and fluvoxamine, especially in patients with severe depression and agitated depression: a case-control study. Int Clin Psychopharmacol 17:53–58

    Article  Google Scholar 

  • Gartside SE, Cowen PJ, Sharp T (1992) Effect of 5-hydroxy-l-tryptophan on the release of 5-HT in rat hypothalamus in vivo as measured by microdialysis. Neuropharmacology 31:9–14

    Article  PubMed  CAS  Google Scholar 

  • Grecksch G, Zhou D, Franke C, Schroder U, Sabel B, Becker A, Huether G (1997) Influence of olfactory bulbectomy and subsequent imipramine treatment on 5-hydroxytryptaminergic presynapses in the rat frontal cortex: behavioural correlates. Br J Pharmacol 122:1725–1731

    Article  PubMed  CAS  Google Scholar 

  • Hasegawa S, Watanabe A, Nguyen KQ, Debonnel G, Diksic M (2005) Chronic administration of citalopram in olfactory bulbectomy rats restores brain 5-HT synthesis rates: an autoradiographic study. Psychopharmacology (Berl) 179:781–790

    Article  CAS  Google Scholar 

  • Ho Y, Liu T, Tai M, Wen Z, Chow RS, Tsai Y, Wong C (2001) Effects of olfactory bulbectomy on NMDA receptor density in the rat brain. Brain Res 900:214–218

    Article  PubMed  CAS  Google Scholar 

  • Ho YJ, Chen KH, Tai MY, Tsai YF (2004) MK-801 suppresses muricidal behavior but not locomotion in olfactory bulbectomized rats: involvement of NMDA receptors. Pharmacol Biochem Behav 77:641–646

    Article  PubMed  CAS  Google Scholar 

  • Kelly JP, Leonard BE (1994) The effect of tianeptine and sertraline in three animal models of depression. Neuropharmacology 33:1011–1116

    Article  PubMed  CAS  Google Scholar 

  • Kelly JP, Wrynn AS, Leonard BE (1997) The olfactory bulbectomized rat as a model of depression: an update. Pharmacol Ther 74:299–316

    Article  PubMed  CAS  Google Scholar 

  • Lumia AR, Teicher MH, Salchli F, Ayers E, Possidente B (1992) Olfactory bulbectomy as a model for agitated hyposerotonergic depression. Brain Res 1587:181–185

    Article  Google Scholar 

  • McGrath C, Norman TR (1998) The effect of venlafaxine treatment on the behavioural and neurochemical changes in the olfactory bulbectomised rat. Psychopharmacology 136:394–401

    Article  PubMed  CAS  Google Scholar 

  • Meoni P, Salinas E, Brault Y, Hackett D (2001) Pattern of symptom improvement following treatment with venlafaxine XR in patients with generalized anxiety disorder. J Clin Psychiatry 62:888–893

    Article  PubMed  CAS  Google Scholar 

  • Mochizuki D, Tsujita R, Yamada S, Kawasaki K, Otsuka Y, Hashimoto S, Hattori T, Kitamura Y, Miki N (2002) Neurochemical and behavioural characterization of milnacipran, a serotonin and noradrenaline reuptake inhibitor in rats. Psychopharmacology 162:323–332

    Article  PubMed  CAS  Google Scholar 

  • Okazawa H, Yamane F, Blier P, Diksic M (1999) Effects of acute and chronic administration of the serotonin1a agonist buspirone on serotonin synthesis in the rat brain. J Neurochem 72:2022–2031

    Article  PubMed  CAS  Google 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. J Pharmacol Exp Ther 289:926–935

    PubMed  CAS  Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167

    Article  PubMed  CAS  Google Scholar 

  • Redmond AM, Kelly JP, Leonard BE (1997) Behavioural and neurochemical effects of dizocilpine in the olfactory bulbectomized rat model of depression. Pharmacol Biochem Behav 58:355–359

    Article  PubMed  CAS  Google Scholar 

  • Redmond AM, Kelly JP, Leonard B (1999) The determination of the optimal dose of milnacipran in the olfactory bulbectomized rat model of depression. Pharmacol Biochem Behav 62:619–623

    Article  PubMed  CAS  Google Scholar 

  • Saitoh A, Yamaguchi K, Murasawa H, Kamei J (2003) The approaches in the discovery of antidepressants using affective disorder models. Japanese Journal of Neuropsychopharmacology 23:75–82

    PubMed  CAS  Google Scholar 

  • Saitoh A, Hirose N, Yamada M, Yamada M, Nozaki C, Oka T, Kamei J (2006) Changes in emotional behavior of mice in the hole-board test after olfactory bulbectomy. J Pharmacol Sci 102:377–386

    Article  PubMed  CAS  Google Scholar 

  • Shibata S, Nakanishi H, Watanabe S, Ueki S (1984) Effects of chronic administration of antidepressants on mouse-killing behavior (muricide) in olfactory bulbectomized rats. Pharmacol Biochem Behav 21:225–230

    Article  PubMed  CAS  Google Scholar 

  • Song C, Leonard BE (1997) Changes in behavior, neurotransmitters and neutrophil function in olfactory bulbectomized rats: Effects of chronic desipramine treatment. Hum Psychopharmacol 12:99–103

    Article  CAS  Google Scholar 

  • Song C, Leonard BE (2005) The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev 29:627–647

    Article  PubMed  Google Scholar 

  • Stahl SM, Grady MM, Moret C, Briley M (2006) SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr 10:732–747

    Google Scholar 

  • Thorne BM, Rowles JS (1988) Memory deficit in passive-avoidance learning in bulbectomized Long–Evans hooded rats. Physiol Behav 44:339–345

    Article  PubMed  CAS  Google Scholar 

  • van der Stelt HM, Breuer ME, Olivier B, Westenberg HG (2005) Permanent deficits in serotonergic functioning of olfactory bulbectomized rats: an in vivo microdialysis study. Biol Psychiatry 57:1061–1067

    Article  PubMed  CAS  Google Scholar 

  • van Riezen H, Leonard BE (1990) Effects of psychotropic drugs on the behavior and neurochemistry of olfactory bulbectomized rats. Pharmacol Ther 47:21–34

    Article  PubMed  Google Scholar 

  • Watanabe A, Tohyama Y, Nguyen KQ, Hasegawa S, Debonnel G, Diksic M (2003) Regional brain serotonin synthesis is increased in the olfactory bulbectomy rat model of depression: an autoradiographic study. J Neurochem 85:469–475

    Article  PubMed  CAS  Google Scholar 

  • Wieronska JM, Papp M, Pilc A (2001) Effects of anxiolytic drugs on some behavioral consequences in olfactory bulbectomized rats. Pol J Pharmacol 53:517–525

    PubMed  CAS  Google Scholar 

  • Yamaguchi K, Murasawa H, Kyuki K (2002) Animal models to elucidate depression and anxiety: usability of hyperemotionality and time on closed-arms of an elevated plus-maze (+maze) in olfactory bulbectomized (OB) rats. Jpn J Pharmacol 88:235

    Google Scholar 

Download references

Acknowledgment

The authors would like to thank Mr. Shinya Kobayashi for their technical assistance.

Author information

Authors and Affiliations

  1. Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo, 142-8501, Japan

    Akiyoshi Saitoh, Noritaka Hirose & Junzo Kamei

  2. Nihon Bioresearch Inc., 6-104 Majima, Fukuju-cho, Hashima, Gifu, 501-6251, Japan

    Kazumasa Yamaguchi, Hiroyasu Murasawa & Akiko Nakatani

  3. Narabyouri Research Co., Ltd., 2631-82, Tsuge Hayama-cho, Nara, Nara, 632-0231, Japan

    Yoshimi Tatsumi

  4. Department of Psychogeriatrics, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan

    Misa Yamada & Mitsuhiko Yamada

Authors
  1. Akiyoshi Saitoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazumasa Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshimi Tatsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyasu Murasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akiko Nakatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Noritaka Hirose
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Misa Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mitsuhiko Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Junzo Kamei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akiyoshi Saitoh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saitoh, A., Yamaguchi, K., Tatsumi, Y. et al. Effects of milnacipran and fluvoxamine on hyperemotional behaviors and the loss of tryptophan hydroxylase-positive cells in olfactory bulbectomized rats. Psychopharmacology 191, 857–865 (2007). https://doi.org/10.1007/s00213-007-0699-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0699-x

Keywords

Search

Navigation