Skip to main content
SpringerLink
Log in

Inter-individual differences in novelty-seeking behavior in rats predict differential responses to desipramine in the forced swim test

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

Abstract

Rationale

Antidepressant medications are effective only in a subpopulation of patients with depression, and some patients respond to certain drugs, but not others. The biological bases for these clinical observations remain unexplained.

Objective

To investigate individual differences in response to antidepressants, we have examined the effects of the norepinephrine reuptake inhibitor desipramine (DMI) and the selective serotonin reutake inhibitor fluoxetine (FLU) in the forced swim test (FST) in rats that differ in their emotional behavior.

Methods

As response to novelty correlates with numerous other measures of emotionality and substance abuse, we contrasted animals that are high responders (HR) in a novel environment with animals that are low responders (LR) and asked whether the two groups exhibit differential responses to DMI (10mg/kg) and FLU (20mg/kg).

Results

At the behavioral level, DMI caused a significant decrease in immobility in LR animals only, while FLU caused a significant reduction in immobility in both groups. Moreover, at the neural level, DMI treatment led to a decrease in FST-induced c-fos messenger RNA levels in medial prefrontal cortex (PFC) and paraventricular nucleus of the hypothalamus (PVN) in LR but not HR animals.

Conclusions

Taken together, our results suggest that the HR-LR model is a useful tool to investigate individual differences in responses to norepinephrine reuptake inhibitors (NRIs) and that a differential activation of PFC and/or PVN could underlie some of the inter-individual differences in the efficacy of NRIs.

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

  • Benedetti F, Bernasconi A, Pontiggia A (2006) Depression and neurological disorders. Curr Opin Psychiatry 19:14–18

    Article  PubMed  Google Scholar 

  • Borsini F (1995) Role of the serotonergic system in the forced swimming test. Neurosci Biobehav Rev 19:377–395

    Article  PubMed  CAS  Google Scholar 

  • Cecchi M, Khoshbouei H, Javors M, Morilak DA (2002) Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuroscience 112:13–21

    Article  PubMed  CAS  Google Scholar 

  • Connor TJ, Kelly JP, Leonard BE (1997) Forced swim test-induced neurochemical endocrine, and immune changes in the rat. Pharmacol Biochem Behav 58:961–967

    Article  PubMed  CAS  Google Scholar 

  • 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 29:547–569

    Article  PubMed  CAS  Google Scholar 

  • Dellu F, Mayo W, Vallee M, Maccari S, Piazza PV, Le Moal M, Simon H (1996) Behavioral reactivity to novelty during youth as a predictive factor of stress-induced corticosterone secretion in the elderly—a life-span study in rats. Psychoneuroendocrinology 21:441–453

    Article  PubMed  CAS  Google Scholar 

  • Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl) 121:66–72

    Article  CAS  Google Scholar 

  • Duncan GE, Knapp DJ, Johnson KB, Breese GR (1996) Functional classification of antidepressants based on antagonism of swim stress-induced fos-like immunoreactivity. J Pharmacol Exp Ther 277:1076–1089

    PubMed  CAS  Google Scholar 

  • Fava M, Davidson KG (1996) Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 19:179–200

    Article  PubMed  CAS  Google Scholar 

  • Isgor C, Cecchi M, Kabbaj M, Akil H, Watson SJ (2003) Estrogen receptor beta in the paraventricular nucleus of hypothalamus regulates the neuroendocrine response to stress and is regulated by corticosterone. Neuroscience 121:837–845

    Article  PubMed  CAS  Google Scholar 

  • Kabbaj M, Devine DP, Savage VR, Akil H (2000) Neurobiological correlates of individual differences in novelty-seeking behavior in the rat: differential expression of stress-related molecules. J Neurosci 20:6983–6988

    PubMed  CAS  Google Scholar 

  • Kirchheiner J, Bertilsson L, Bruus H, Wolff A, Roots I, Bauer M (2003) Individualized medicine—implementation of pharmacogenetic diagnostics in antidepressant drug treatment of major depressive disorders. Pharmacopsychiatry 36(Suppl 3):S235–S243

    PubMed  CAS  Google Scholar 

  • Kostowski W, Danysz W, Plaznik A, Nowakowska E (1984) Studies on the locus coeruleus system in an animal model for antidepressive activity. Pol J Pharmacol Pharm 36:523–530

    PubMed  CAS  Google Scholar 

  • Loy R, Koziell DA, Lindsey JD, Moore RY (1980) Noradrenergic innervation of the adult rat hippocampal formation. J Comp Neurol 189:699–710

    Article  PubMed  CAS  Google Scholar 

  • Moore RY, Bloom FE (1979) Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu Rev Neurosci 2:113–168

    Article  PubMed  CAS  Google Scholar 

  • Nyback HV, Walters JR, Aghajanian GK, Roth RH (1975) Tricyclic antidepressants: effects on the firing rate of brain noradrenergic neurons. Eur J Pharmacol 32:302–312

    Article  PubMed  CAS  Google Scholar 

  • Piazza PV, Deminiere JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732

    Article  PubMed  CAS  Google Scholar 

  • Ressler KJ, Nemeroff CB (2000) Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12(Suppl 1):2–19

    Article  PubMed  Google Scholar 

  • Rosario LA, Abercrombie ED (1999) Individual differences in behavioral reactivity: correlation with stress-induced norepinephrine efflux in the hippocampus of Sprague–Dawley rats. Brain Res Bull 48:595–602

    Article  PubMed  CAS  Google Scholar 

  • Scuvee-Moreau JJ, Dresse AE (1979) Effect of various antidepressant drugs on the spontaneous firing rate of locus coeruleus and dorsal raphe neurons of the rat. Eur J Pharmacol 57:219–225

    Article  PubMed  CAS  Google Scholar 

  • Stead JD, Clinton S, Neal C, Schneider J, Jama A, Miller S, Vazquez DM, Watson SJ, Akil H (2006) Selective breeding for divergence in novelty-seeking traits: heritability and enrichment in spontaneous anxiety-related behaviors. Behav Genet 36:697–712

    Article  PubMed  Google Scholar 

  • Taghzouti K, Lamarque S, Kharouby M, Simon H (1999) Interindividual differences in active and passive behaviors in the forced-swimming test: implications for animal models of psychopathology. Biol Psychiatry 45:750–758

    Article  PubMed  CAS  Google Scholar 

  • Thierry B, Steru L, Chermat R, Simon P (1984) Searching-waiting strategy: a candidate for an evolutionary model of depression? Behav Neural Biol 41:180–189

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank James Stewart for his excellent technical assistance.

Author information

Authors and Affiliations

  1. St Elizabeths Hospital, 2700 M.L. King Ave SE, Barton Hall, 2nd Floor, Washington, DC, 20032, USA

    A. Jama

  2. Molecular and Behavioral Neuroscience Institute, The University of Michigan School of Medicine, 205 Zina Pitcher Place, Ann Arbor, MI, 48109-0720, USA

    M. Cecchi, N. Calvo, S. J. Watson & H. Akil

Authors
  1. A. Jama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Cecchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Calvo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. J. Watson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Akil
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Cecchi.

Additional information

This work was supported by Office of Naval Research grant N00014-02-1-0879 and NIDA R01 DA 13386 to Huda Akil, and by NIMH P01 MH42251 to Stanley J. Watson.

A. Jama and M. Cecchi contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jama, A., Cecchi, M., Calvo, N. et al. Inter-individual differences in novelty-seeking behavior in rats predict differential responses to desipramine in the forced swim test. Psychopharmacology 198, 333–340 (2008). https://doi.org/10.1007/s00213-008-1126-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1126-7

Keywords

Search

Navigation