Skip to main content
SpringerLink
Log in

Effects of chronic antidepressant treatments in a putative genetic model of vulnerability (Roman low-avoidance rats) and resistance (Roman high-avoidance rats) to stress-induced depression

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

Abstract

Introduction

The Roman low- (RLA) and high-avoidance (RHA) rats were selectively bred for, respectively, poor versus rapid acquisition of active avoidance in a shuttle box and, under aversive conditions, display reactive (RLA) versus proactive (RHA) coping behaviors. In the forced swim test (FST), RLA rats exhibit a depression-like behavior characterized by greater immobility and fewer climbing counts when compared with their RHA counterparts. Furthermore, subacute treatments with clinically effective antidepressant drugs decrease immobility and increase climbing or swimming in RLA rats but do not modify the performance of RHA rats.

Objective and methods

Because chronic treatment with antidepressants is usually required to produce clinical effects, the present study was designed to compare the behaviors of RLA and RHA rats in the FST after subacute (1 day) and chronic (15 days) administration of desipramine, fluoxetine, and chlorimipramine.

Results

In RLA rats, subacute treatments with low doses of desipramine, fluoxetine, and chlorimipramine (2.5–5 mg/kg) were ineffective whereas chronic treatments with the same doses of all three antidepressants decreased immobility and also increased climbing (desipramine) or swimming (fluoxetine). By contrast, neither subacute nor chronic treatments with these antidepressants induced significant changes in the behavior of RHA rats in the FST.

Conclusions

RLA and RHA rats represent two divergent phenotypes, respectively susceptible and resistant to develop depression-like behavior under aversive environmental conditions that may be used to identify genetically determined neural substrates and mechanisms underlying vulnerability and resistance to stress-induced depression.

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

Similar content being viewed by others

References

  • aan het Rot M, Mathew SJ, Charney DS (2009) Neurobiological mechanisms in major depressive disorder. CMAJ 180:305–313. doi:10.1503/cmaj.080697

    Article  PubMed Central  PubMed  Google Scholar 

  • Alcaro A, Cabib S, Ventura R, Puglisi-Allegra S (2002) Genotype- and experience-dependent susceptibility to depressive-like responses in the forced-swimming test. Psychopharmacology 164:138–143. doi:10.1007/s00213-002-1161-8

    Article  CAS  PubMed  Google Scholar 

  • Anisman H, Matheson K (2005) Stress, depression, and anhedonia: caveats concerning animal models. Neurosci Biobehav Rev 29:525–546. doi:10.1016/j.neubiorev.2005.03.007

    Article  PubMed  Google Scholar 

  • Anraku T, Ikegaya Y, Matsuki N, Nishiyama N (2001) Withdrawal from chronic morphine administration causes prolonged enhancement of immobility in rat forced swimming test. Psychopharmacology 157:217–220. doi:10.1007/s002130100793

    Article  CAS  PubMed  Google Scholar 

  • Armario A, Gavaldà A, Martí J (1995) Comparison of the behavioural and endocrine response to forced swimming stress in five inbred strains of rats. Psychoneuroendocrinology 20:879–890. doi:10.1016/0306-4530(95)00018-6

    Article  CAS  PubMed  Google Scholar 

  • Boersma GJ, Benthem L, van Dijk G, Scheurink AJ (2011) Individual variation in the (patho)physiology of energy balance. Physiol Behav 103:89–97. doi:10.1016/j.physbeh.2010.12.026

    Article  CAS  PubMed  Google Scholar 

  • 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 97:183–188. doi:10.1007/BF00442247

    Article  CAS  PubMed  Google Scholar 

  • Broadhurst PI, Bignami G (1964) Correlative effects of psychogenetic selection: a study of the Roman high- and low-avoidance strains of rats. Behav Res Ther 2:273–280. doi:10.1016/0005-7967(64)90033-6

    Article  Google Scholar 

  • Carrasco J, Márquez C, Nadal R, Tobeña A, Fernández-Teruel A, Armario A (2008) Characterization of central and peripheral components of the hypothalamus–pituitary–adrenal axis in the inbred Roman rat strains. Psychoneuroendocrinology 33:437–445. doi:10.1016/j.psyneuen.2008.01.001

    Article  CAS  PubMed  Google Scholar 

  • Caspi A, Moffitt TE (2006) Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci 7:583–590. doi:10.1038/nm1925

    Article  CAS  PubMed  Google Scholar 

  • Charney DS, Manji HK (2004) Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE (225):re5. doi:10.1126/stke.2252004re5

  • Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, Ferguson D, Tsai HC, Pomeranz L, Christoffel DJ, Nectow AR, Ekstrand M, Domingos A, Mazei-Robison MS, Mouzon E, Lobo MK, Neve RL, Friedman JM, Russo SJ, Deisseroth K, Nestler EJ, Han MH (2013) Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493:532–536. doi:10.1038/nature11713

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Crabbe JC, Wahlsten D, Dudek BC (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284:1670–1672. doi:10.1126/science.284.5420.1670

    Google Scholar 

  • Cryan JF, Hoyer D, Markou A (2003) Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biol Psychiatry 54:49–58. doi:10.1016/S0006-3223(02)01730-4

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Page ME, Lucki I (2005a) Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment. Psychopharmacology 182:335–344. doi:10.1007/s00213-005-0093-5

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Valentino RJ, Lucki I (2005b) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29:547–569. doi:10.1016/j.neubiorev.2005.03.008

    Article  CAS  PubMed  Google Scholar 

  • D’Angio M, Serrano A, Driscoll P, Scatton B (1988) Stressful environmental stimuli increase extracellular DOPAC levels in the prefrontal cortex of hypoemotional (Roman high-avoidance) but not hyperemotional (Roman low-avoidance) rats. An in vivo voltammetric study. Brain Res 451:237–247. doi:10.1016/0006-8993(88)90768-8

    Article  PubMed  Google Scholar 

  • Delgado PL, Moreno FA (2000) Role of norepinephrine in depression. J Clin Psychiatry 61(Suppl 1):5–12

    CAS  PubMed  Google Scholar 

  • 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 5:107–112. doi:10.1037/1064-1297.5.2.107

    Article  CAS  PubMed  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 121:66–72. doi:10.1007/BF02245592

    Article  CAS  PubMed  Google Scholar 

  • Driscoll P, Bättig K (1982) Behavioral, emotional and neurochemical profiles of rats selected for extreme differences in active, two-way avoidance performance. In: Lieblich I (ed) Genetics of the Brain. Elsevier, Amsterdam, pp 95–123

    Google Scholar 

  • Driscoll P, Fernández-Teruel A, Corda MG, Giorgi O, Steimer T (2009) Some guidelines for defining personality differences in rats. In: Kim Y-K (ed) Handbook of behavior genetics. Springer, New York, pp 281–300. ISBN 978-0-387-76726-0

    Chapter  Google Scholar 

  • Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64:327-337. ISSN: 0003-990X (print), 1538-3636 (electronic)

  • El Yacoubi M, Bouali S, Popa D, Naudon L, Leroux-Nicollet I, Hamon M, Costentin J, Adrien J, Vaugeois JM (2003) Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression. Proc Natl Acad Sci USA 100:6227–6232. doi:10.1073/pnas.1034823100

    Article  PubMed  Google Scholar 

  • Escorihuela RM, Tobeña A, Driscoll P, Fernández-Teruel A (1995) Effects of training, early handling, and perinatal flumazenil on shuttle box acquisition in Roman low-avoidance rats: toward overcoming a genetic deficit. Neurosci Biobehav Rev 19:353-367. doi:10.1016/0149-7634(94)00051-2

    Google Scholar 

  • Escorihuela RM, Fernández-Teruel A, Gil L, Aguilar R, Tobeña A, Driscoll P (1999) Inbred Roman high- and low-avoidance rats: differences in anxiety, novelty-seeking, and shuttlebox behaviors. Physiol Behav 67:19–26. doi:10.1016/S0031-9384(99)00064-5

    Article  CAS  PubMed  Google Scholar 

  • Fattore L, Piras G, Corda MG, Giorgi O (2009) The Roman high- and low-avoidance rat lines differ in the acquisition, maintenance, extinction, and reinstatement of intravenous cocaine self-administration. Neuropsychopharmacology 34:1091–1101. doi:10.1038/npp.2008.43

    Article  CAS  PubMed  Google Scholar 

  • Feder A, Nestler EJ, Charney DS (2009) Psychobiology and molecular genetics of resilience. Nat Rev Neurosci 10:446–457. doi:10.1038/nrn2649

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fernández-Teruel A, Driscoll P, Gil L, Aguilar R, Tobeña A, Escorihuela RM (2002) Enduring effects of environmental enrichment on novelty seeking, saccharin and ethanol intake in two rat lines (RHA/Verh and RLA/Verh) differing in incentive-seeking behavior. Pharmacol Biochem Behav 73:225–231. doi:10.1016/S0091-3057(02)00784-0

    Article  PubMed  Google Scholar 

  • Ferré P, Fernández-Teruel A, Escorihuela RM, Driscoll P, Corda MG, Giorgi O, Tobeña A (1995) Behavior of the Roman/Verh high- and low-avoidance rat lines in anxiety tests: relationship with defecation and self-grooming. Physiol Behav 58:1209–1213. doi:10.1016/0031-9384(95)02068-3

    Article  PubMed  Google Scholar 

  • Gelfin Y, Gorfine M, Lerer B (1998) Effect of clinical doses of fluoxetine on psychological variables in healthy volunteers. Am J Psychiatry 155:290–292. http://ajp.psychiatryonline.org/cgi/content/full/155/2/290

    Google Scholar 

  • Gentsch C, Lichtsteiner M, Driscoll P, Feer H (1982) Differential hormonal and physiological responses to stress in Roman high- and low-avoidance rats. Physiol Behav 28:259–263. doi:10.1016/0031-9384(82)90072-5

    Article  CAS  PubMed  Google Scholar 

  • Gentsch C, Lichtsteiner M, Feer H (1991) Genetic and environmental influences on reactive and spontaneous locomotor activities in rats. Experientia 47:998–1008

    Article  CAS  PubMed  Google Scholar 

  • Giorgi O, Lecca D, Piras G, Driscoll P, Corda MG (2003) Dissociation between mesocortical dopamine release and fear-related behaviors in two psychogenetically selected lines of rats that differ in coping strategies to aversive conditions. Eur J Neurosci 17:2716–2726. doi:10.1046/j.1460-9568.2003.02689.x

    Article  CAS  PubMed  Google Scholar 

  • Giorgi O, Piras G, Lecca D, Corda MG (2005) Differential activation of dopamine release in the nucleus accumbens core and shell after acute or repeated amphetamine injections: a comparative study in the Roman high- and low-avoidance rat lines. Neuroscience 135:987–998. doi:10.1016/j.neuroscience.2005.06.075

    Article  CAS  PubMed  Google Scholar 

  • Giorgi O, Piras G, Corda MG (2007) The psychogenetically selected Roman high- and low-avoidance rat lines: a model to study the individual vulnerability to drug addiction. Neurosci Biobehav Rev 31:148–163

    Google Scholar 

  • 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 282:727–733

    CAS  PubMed  Google Scholar 

  • Hill MN, Brotto LA, Lee TT, Gorzalka BB (2003) Corticosterone attenuates the antidepressant-like effects elicited by melatonin in the forced swim test in both male and female rats. Prog Neuropsychopharmacol Biol Psychiatry 27:905–911

    Article  CAS  PubMed  Google Scholar 

  • Hoge EA, Austin ED, Pollack MH (2007) Resilience: research evidence and conceptual considerations for posttraumatic stress disorder. Depress Anxiety 24:139–152. doi:10.1002/da.20175

    Article  PubMed  Google Scholar 

  • Ilango A, Shumake J, Wetzel W, Scheich H, Ohl FW (2012) The role of dopamine in the context of aversive stimuli with particular reference to acoustically signaled avoidance learning. Front Neurosci 6:132. doi:10.3389/fnins.2012.00132

    Article  PubMed Central  PubMed  Google Scholar 

  • 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 29:566–579. doi:10.1038/sj.npp.1300341

    Article  CAS  PubMed  Google Scholar 

  • Kendler KS, Karkowski LM, Prescott CA (1999) Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 156:837–841. http://ajp.psychiatryonline.org/cgi/content/full/156/6/837

    Google Scholar 

  • Lecca D, Piras G, Driscoll P, Giorgi O, Corda MG (2004) A differential activation of dopamine output in the shell and core of the nucleus accumbens is associated with the motor responses to addictive drugs: a brain dialysis study in Roman high- and low-avoidance rats. Neuropharmacology 46:688–699. doi:10.1016/j.neuropharm.2003.11.011

    Article  CAS  PubMed  Google Scholar 

  • López-Aumatell R, Vicens-Costa E, Guitart-Masip M, Martínez-Membrives E, Valdar W, Johannesson M, Cañete T, Blázquez G, Driscoll P, Flint J, Tobeña A, Fernández-Teruel A (2009) Unlearned anxiety predicts learned fear: a comparison among heterogeneous rats and the Roman rat strains. Behav Brain Res 202:92–101. doi:10.1016/j.bbr.2009.03.024

    Article  PubMed  Google Scholar 

  • Lucki I (1997) The forced swimming test as a model for core and component behavioural effects of antidepressant drugs. Behav Pharmacol 8:523–532. http://journals.lww.com/behaviouralpharm/Abstract/1997/11000

  • Moreno M, Cardona D, Gómez MJ, Sánchez-Santed F, Tobeña A, Fernández-Teruel A, Campa L, Suñol C, Escarabajal MD, Torres C, Flores P (2010) Impulsivity characterization in the Roman high- and low-avoidance rat strains: behavioral and neurochemical differences. Neuropsychopharmacology 35:1198–1208. doi:10.1038/npp.2009.224

    Article  PubMed  Google Scholar 

  • Overstreet DH, Friedman E, Mathe AA, Yadid G (2005) The Flinders Sensitive Line rats: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 29:739–759. doi:10.1016/j.neubiorev.200503.015

    Article  CAS  PubMed  Google Scholar 

  • Papaioannou A, Gerozissis K, Prokopiou A, Bolaris S, Stylianopoulou F (2002) Sex differences in the effects of neonatal handling on the animal’s response to stress and the vulnerability for depressive behaviour. Behav Brain Res 129:131–139. doi:10.1016/50166-4328(01)00334-5

    Article  CAS  PubMed  Google Scholar 

  • Piras G, Giorgi O, Corda MG (2010) Effects of antidepressants on the performance in the forced swim test of two psychogenetically selected lines of rats that differ in coping strategies to aversive conditions. Psychopharmacology (Berl) 211:403–414. doi:10.1007/s00213-010-1904-x

    Article  CAS  Google Scholar 

  • Piras G, Lecca D, Corda MG, Giorgi O (2003) Repeated morphine injections induce behavioral sensitization in Roman high- but not in Roman low-avoidance rats. Neuroreport 14:2433–2438

    Article  CAS  PubMed  Google Scholar 

  • Poldinger W (1963) Comparison between imipramine and desipramine in normal subjects and their action in depressive patients. Psychopharmacologia 4:302–307. doi:10.1007/BF00408186

    Article  Google Scholar 

  • Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732. doi:10.1038/266730a0

    Article  CAS  PubMed  Google Scholar 

  • Rénéric JP, Lucki I (1998) Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacology (Berl) 136:190–197

    Article  Google Scholar 

  • Risch N et al (2009) Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression. A meta-analysis JAMA 301:2462–2471. doi:10.1001/jama.2009.878

    CAS  Google Scholar 

  • Rygula R, Abumaria N, Flügge G, Hiemke C, Fuchs E, Rüther E (2006) Havemann-Reinecke U (2006) Citalopram counteracts depressive-like symptoms evoked by chronic social stress in rats. Behav Pharmacol 17:19–29

    Article  CAS  PubMed  Google Scholar 

  • Siegel J (1997) Augmenting and reducing of visual evoked potentials in high- and low-sensation seeking humans, cats, and rats. Behav Genet 27:557–563. doi:10.1023/A:1021409132320

    Article  CAS  PubMed  Google Scholar 

  • Slattery DA, Cryan JF (2012) Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat Protoc 7:1009–1014. doi:10.1038/nprot.2012.044

    Article  CAS  PubMed  Google Scholar 

  • Stark H, Rothe T, Wagner T, Scheich H (2004) Learning a new behavioral strategy in the shuttle-box increases prefrontal dopamine. Neuroscience 126:21–29. doi:10.1016/j.neuroscience.2004.02.026

    Article  CAS  PubMed  Google Scholar 

  • Steimer T, Driscoll P (2003) Divergent stress responses and coping styles in psychogenetically selected Roman high- (RHA) and low- (RLA) avoidance rats: behavioural, neuroendocrine and developmental aspects. Stress 6:87–100. doi:10.1080/1025389031000111320

    Article  CAS  PubMed  Google Scholar 

  • Steimer T, Driscoll P (2005) Inter-individual vs line/strain differences in psychogenetically selected Roman high- (RHA) and low- (RLA) avoidance rats: behavioural, neuroendocrine and developmental aspects. Neurosci Biobehav Rev 29:99–112

    Article  PubMed  Google Scholar 

  • Steimer T, Python A, Schulz PE, Aubry JM (2007) Plasma corticosterone, dexamethasone (DEX) suppression and DEX/CRH tests in a rat model of genetic vulnerability to depression. Psychoneuroendocrinology 32:575–579. doi:10.1016/j.psyneuen.2007.03.012

    Article  CAS  PubMed  Google Scholar 

  • Velázquez-Moctezuma J, Diaz Ruiz O (1992) Neonatal treatment with clomipramine increased immobility in the forced swim test: an attribute of animal models of depression. Pharmacol Biochem Behav 42:737–739

    Article  PubMed  Google Scholar 

  • Weiss JM, Cierpial MA, West CH (1998) Selective breeding of rats for high and low motor activity in a swim test: toward a new animal model of depression. Pharmacol Biochem Behav 61:49–66. doi:10.1016/S0091-3057(98)00075-6

    Article  CAS  PubMed  Google Scholar 

  • Will CC, Aird F, Redei EE (2003) Selectively bred Wistar–Kyoto rats: an animal model of depression and hyper-responsiveness to antidepressants. Mol Psychiatry 8:925–932. doi:10.1038/sj.mp.4001345

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partially supported by grants from the Italian Ministry of the University and Research (MIUR) to OG and MGC and from ARS (Autonomous Region of Sardinia) (L.R. 7/2007, “Promotion of Scientific Research and technological innovation in Sardinia,” European Social Fund, 2007–2013, Project Code No. CRP-59842) to OG.

Author information

Author notes

  1. Giovanna Piras

    Present address: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy

Authors and Affiliations

  1. Department of Life and Environmental Sciences, Section of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy

    Maria A. Piludu, Osvaldo Giorgi & Maria G. Corda

Authors
  1. Giovanna Piras
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria A. Piludu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Osvaldo Giorgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria G. Corda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Osvaldo Giorgi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Piras, G., Piludu, M.A., Giorgi, O. et al. Effects of chronic antidepressant treatments in a putative genetic model of vulnerability (Roman low-avoidance rats) and resistance (Roman high-avoidance rats) to stress-induced depression. Psychopharmacology 231, 43–53 (2014). https://doi.org/10.1007/s00213-013-3205-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3205-7

Keywords

Search

Navigation