Psychopharmacology

, Volume 182, Issue 3, pp 335–344 | Cite as

Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment

Original Investigation

Abstract

Rationale

The forced swim test (FST) is the most widely used model for assessing potential antidepressant activity in rodents following acute or short-term treatment. However, few studies have compared the effects of short- and long-term antidepressant treatment on behaviors in the test, despite the need to treat patients chronically to produce clinical effects.

Objectives

The current studies examined whether antidepressants from different classes produce different behavioral effects following short-term treatment and whether such effects change following administration for a longer duration.

Methods

The effects of administering short-term (3 days) and long-term (14 days) treatments of antidepressants from three different chemical classes with distinct mechanisms of action via osmotic minipump were examined: the selective norepinephrine reuptake inhibitor reboxetine (10 and 60 mg kg−1 day−1), the selective serotonin reuptake inhibitor fluoxetine (2.5 and 15 mg kg−1 day−1), and the reversible inhibitor of monoamine oxidase moclobemide (2.5 and 15 mg kg−1 day−1). All testing was carried out in a 15-min test with no preswim session in order to negate any confounding aspect of an induction procedure.

Results

The majority of antidepressant-sensitive behavioral changes were observed in the first 5 min of the test. The low dose of reboxetine failed to alter behavior in the test after 3 days but significantly decreased immobility and increased climbing behavior following administration for 14 days, whereas the high dose of reboxetine was equally effective following 3 and 14 days of treatment. In a similar fashion, the low dose of fluoxetine failed to alter behavior in the test following 3 days, but showed an augmented response on immobility and increased swimming following administration for 14 days. The high dose of fluoxetine was slightly more effective at reducing immobility following administration for 14 days than 3 days. The low dose of moclobemide decreased immobility and increased climbing behavior following treatment for 3 days, but increases in both swimming and climbing behaviors were measured following treatment for 14 days. Treatment with the high dose of moclobemide for 3 days decreased immobility and increased swimming, whereas treatment for 14 days significantly increased both active behaviors (swimming and climbing).

Conclusions

Antidepressants from three different classes produce different effects on active behaviors in the FST. The effects of antidepressants were augmented following chronic administration for 14 days, especially when given at low doses. This suggests that modifications of the FST can be used to examine the onset of action of antidepressant agents produced by long-term administration.

Keywords

Antidepressant Noradrenergic Serotonergic Forced swimming test Animal model 

References

  1. Alvarez JC, Sanceaume M, Advenier C, Spreux-Varoquaux O (1999) Differential changes in brain and platelet 5-HT concentrations after steady-state achievement and repeated administration of antidepressant drugs in mice. Eur Neuropsychopharmacol 10:31–36PubMedCrossRefGoogle Scholar
  2. Benmansour S, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, Frazer A (1999) Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. J Neurosci 19:10494–10501PubMedGoogle Scholar
  3. Benmansour S, Owens WA, Cecchi M, Morilak DA, Frazer A (2002) Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter. J Neurosci 22:6766–6772PubMedGoogle Scholar
  4. Borsini F, Meli A (1988) Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology (Berl) 94:147–160CrossRefGoogle Scholar
  5. Borsini F, Lecci A, Sessarego A, Frassine R, Meli A (1989) Discovery of antidepressant activity by forced swimming test may depend on pre-exposure of rats to a stressful situation. Psychopharmacology (Berl) 97:183–188CrossRefGoogle Scholar
  6. Caldarone BJ, Karthigeyan K, Harrist A, Hunsberger JG, Wittmack E, King SL, Jatlow P, Picciotto MR (2003) Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6J mice. Psychopharmacology (Berl) 170:94–101CrossRefGoogle Scholar
  7. Connor TJ, Kelliher P, Harkin A, Kelly JP, Leonard BE (1999) Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat. Eur J Pharmacol 379:125–133PubMedCrossRefGoogle Scholar
  8. Cryan JF, Lucki I (2000) Antidepressant-like behavioral effects mediated by 5-Hydroxytryptamine(2C) receptors. J Pharmacol Exp Ther 295:1120–1126PubMedGoogle Scholar
  9. Cryan JF, Mombereau C (2004) In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiatry 9:326–357CrossRefPubMedGoogle Scholar
  10. Cryan JF, Markou A, Lucki I (2002a) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245CrossRefPubMedGoogle Scholar
  11. Cryan JF, Page ME, Lucki I (2002b) Noradrenergic lesions differentially alter the antidepressant-like effects of reboxetine in a modified forced swim test. Eur J Pharmacol 436:197–205CrossRefPubMedGoogle Scholar
  12. Cryan JF, Hoyer D, Markou A (2003) Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biol Psychiatry 54:49–58CrossRefPubMedGoogle Scholar
  13. Cryan JF, Valentino RJ, Lucki I (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29:547–569CrossRefPubMedGoogle Scholar
  14. De Pablo JM, Parra A, Segovia S, Guillamon A (1989) Learned immobility explains the behavior of rats in the forced swimming test. Physiol Behav 46:229–237CrossRefPubMedGoogle Scholar
  15. Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl) 121:66–72CrossRefGoogle Scholar
  16. Detke MJ, Johnson J, Lucki I (1997) Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression. Exp Clin Psychopharmacol 5:107–112CrossRefPubMedGoogle Scholar
  17. Dulawa SC, Holick KA, Gundersen B, Hen R (2004) Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology 29:1321–1330CrossRefPubMedGoogle Scholar
  18. Einat H, Karbovski H, Korik J, Tsalah D, Belmaker RH (1999) Inositol reduces depressive-like behaviors in two different animal models of depression. Psychopharmacology (Berl) 144:158–162CrossRefGoogle Scholar
  19. Ferigolo M, Barros HM, Marquardt AR, Tannhauser M (1998) Comparison of behavioral effects of moclobemide and deprenyl during forced swimming. Pharmacol Biochem Behav 60:431–437CrossRefPubMedGoogle Scholar
  20. Gilbert P, Allan S (1998) The role of defeat and entrapment (arrested flight) in depression: an exploration of an evolutionary view. Psychol Med 28:585–598CrossRefPubMedGoogle Scholar
  21. Harkin A, Kelly JP, McNamara M, Connor TJ, Dredge K, Redmond A, Leonard BE (1999) Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression. Eur J Pharmacol 364:123–132PubMedCrossRefGoogle Scholar
  22. Harmer CJ, Bhagwagar Z, Perrett DI, Vollm BA, Cowen PJ, Goodwin GM (2003) Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology 28:148–152CrossRefPubMedGoogle Scholar
  23. Hemby SE, Lucki I, Gatto G, Singh A, Thornley C, Matasi J, Kong N, Smith JE, Davies HM, Dworkin SI (1997) Potential antidepressant effects of novel tropane compounds, selective for serotonin or dopamine transporters. J Pharmacol Exp Ther 282:727–733PubMedGoogle Scholar
  24. Katz MM, Tekell JL, Bowden CL, Brannan S, Houston JP, Berman N, Frazer A (2004) Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology 29:566–579CrossRefPubMedGoogle Scholar
  25. Kelliher P, Kelly JP, Leonard BE, Sanchez C (2003) Effects of acute and chronic administration of selective monoamine re-uptake inhibitors in the rat forced swim test. Psychoneuroendocrinology 28:332–347CrossRefPubMedGoogle Scholar
  26. Kumagae Y, Matsui Y, Iwata N (1991) Deamination of norepinephrine, dopamine, and serotonin by type A monoamine oxidase in discrete regions of the rat brain and inhibition by RS-8359. Jpn J Pharmacol 55:121–128PubMedCrossRefGoogle Scholar
  27. Leonard BE (1998) Animal models of depression. In: Briley M, Montgomery SA (eds) Antidepressant therapy—at the dawn of the third millenium. Martin Dunitz, London, pp 87–109Google Scholar
  28. Lucki I (1997) The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol 8:523–532PubMedCrossRefGoogle Scholar
  29. Lucki I, O'Leary OF (2004) Distinguishing roles for norepinephrine and serotonin in the behavioral effects of antidepressant drugs. J Clin Psychiatry 65(Suppl 4):11–24PubMedGoogle Scholar
  30. Lucki I, Dalvi A, Mayorga AJ (2001) Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. Psychopharmacology (Berl) 155:315–322CrossRefGoogle Scholar
  31. Nestler EJ, Gould E, Manji H, Buncan M, Duman RS, Greshenfeld HK, Hen R, Koester S, Lederhendler I, Meaney M, Robbins T, Winsky L, Zalcman S (2002) Preclinical models: status of basic research in depression. Biol Psychiatry 52:503–528CrossRefPubMedGoogle Scholar
  32. Page ME, Detke MJ, Dalvi A, Kirby LG, Lucki I (1999) Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test. Psychopharmacology (Berl) 147:162–167CrossRefGoogle Scholar
  33. Pineyro G, Blier P (1999) Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev 51:533–591PubMedGoogle Scholar
  34. Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732CrossRefPubMedGoogle Scholar
  35. Reneric JP, Lucki I (1998) Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacology (Berl) 136:190–197CrossRefGoogle Scholar
  36. Reneric JP, Bouvard M, Stinus L (2002) In the rat forced swimming test, chronic but not subacute administration of dual 5-HT/NA antidepressant treatments may produce greater effects than selective drugs. Behav Brain Res 136:521–532CrossRefPubMedGoogle Scholar
  37. Rupniak NM (2003) Animal models of depression: challenges from a drug development perspective. Behav Pharmacol 14:385–390PubMedGoogle Scholar
  38. Thierry B, Steru L, Chermat R, Simon P (1984) Searching–waiting strategy: a candidate for an evolutionary model of depression? Behav Neural Biol 41:180–189CrossRefPubMedGoogle Scholar
  39. Tizabi Y, Overstreet DH, Rezvani AH, Louis VA, Clark E Jr, Janowsky DS, Kling MA (1999) Antidepressant effects of nicotine in an animal model of depression. Psychopharmacology (Berl) 142:193–199CrossRefGoogle Scholar
  40. Vazquez-Palacios G, Bonilla-Jaime H, Velazquez-Moctezuma J (2004) Antidepressant-like effects of the acute and chronic administration of nicotine in the rat forced swimming test and its interaction with flouxetine. Pharmacol Biochem Behav 78:165–169CrossRefPubMedGoogle Scholar
  41. Weinstock M, Poltyrev T, Bejar C, Youdim MB (2002) Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression. Psychopharmacology (Berl) 160:318–324CrossRefGoogle Scholar
  42. Weiss J, Kilts C (1998) Animal models of depression and schizophrenia. In: Nemeroff C, Schatzberg A (eds) Textbook of psychopharmacology. American Psychiatric Association Press, New York, pp 88–123Google Scholar
  43. West AP (1990) Neurobehavioral studies of forced swimming: the role of learning and memory in the forced swim test. Prog Neuro-psychopharmacol Biol Psychiatry 14:863–877CrossRefGoogle Scholar
  44. Willner P, Mitchell P (2002) Animal models of depression: a diathesis/stress approach. In: D'haenen H, Den Boer J, Willner P (eds) Biological psychiatry. Wiley, New York, pp 703–726Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • John F. Cryan
    • 1
    • 3
  • Michelle E. Page
    • 1
    • 4
  • Irwin Lucki
    • 1
    • 2
  1. 1.Department of PsychiatryUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of PharmacologyUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Nervous Systems Research, Novartis Institutes for BioMedical SciencesNovartis Pharma AGBaselSwitzerland
  4. 4.Department of NeurosurgeryThomas Jefferson UniversityPhiladelphiaUSA

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