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Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats

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Abstract

Rationale

The pharmacological treatment of depression in children and adolescents is different from that of adults due to the lack of efficacy of certain antidepressants in the pediatric age group. Our current understanding of why these differences occur is very limited.

Objectives

To develop more effective treatments, a juvenile animal model of depression was tested to validate it as a possible model to specifically study pediatric depression.

Materials and methods

Procedures for use with juvenile rats at postnatal day (PND) 21 and 28 were adapted from the adult learned helplessness model in which, 24 h after exposure to inescapable stress, animals are unable to remove themselves from an easily escapable stressor. Rats were treated for 7 days with either the selective serotonin reuptake inhibitor escitalopram at 10 mg/kg or the tricyclic antidepressant desipramine at 3, 10, or 15 mg/kg to determine if treatment could decrease escape latency times.

Results

Escitalopram treatment was effective at decreasing escape latency times in all ages tested. Desipramine treatment did not decrease escape latency times for PND 21 rats, but did decrease times for PND 28 and adult animals.

Conclusions

The learned helplessness model with PND 21 rats predicts the efficacy of escitalopram and the lack of efficacy of desipramine seen in the treatment of pediatric depression. These findings suggest that the use of PND 21 rats in a modified learned helplessness procedure may be a valuable model of human pediatric depression that can predict pediatric antidepressant efficacy and be used to study antidepressant mechanisms involved in pediatric depression.

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References

  • Amat J, Paul E, Watkins LR, Maier SF (2008) Activation of the ventral medial prefrontal cortex during an uncontrollable stressor reproduces both the immediate and long-term protective effects of behavioral control. Neuroscience 154:1178–1186

    Article  PubMed  CAS  Google Scholar 

  • Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA (2004) Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306:879–881

    Article  PubMed  CAS  Google Scholar 

  • Ansorge MS, Morelli E, Gingrich JA (2008) Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice. J Neurosci 28(1):199–207

    Article  PubMed  CAS  Google Scholar 

  • Birmaher B (1998) Should we use antidepressant medications for children and adolescents with depressive disorders? Psychopharmacol Bull 34:35–39

    PubMed  CAS  Google Scholar 

  • Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J (1996) Childhood and adolescent depression: a review of the past 10 years. Part II. J Am Acad Child Adolesc Psychiatry 35:1575–1583

    Article  PubMed  CAS  Google Scholar 

  • Branchi I, Santucci D, Alleva E (2006) Analysis of ultrasonic vocalizations emitted by infant rodents, chapter 13.2. In: Costa LG, Hodgson E, Lawrence DA, Reed DJ (eds) Current protocols in toxicology. Wiley, Hoboken

    Google Scholar 

  • Chen H, Pandey GN, Dwivedi Y (2006) Hippocampal cell proliferation regulation by repeated stress and antidepressants. Neuroreport 17:863–867

    Article  PubMed  Google Scholar 

  • Chourbaji S, Zacher C, Sanchis-Segura C, Dormann C, Vollmayr B, Gass P (2005) Learned helplessness: validity and reliability of depressive-like states in mice. Brain Res Protoc 16:70–78

    Article  CAS  Google Scholar 

  • Christianson JP, Paul ED, Irani M, Thompson BM, Kubala KH, Yirmiya R, Watkins LR, Maier SF (2008) The role of prior stressor controllability and the dorsal raphe nucleus in sucrose preference and social exploration. Behav Brain Res 193:87–93

    Article  PubMed  Google Scholar 

  • Coyle JT, Pine DS, Charney DS, Lewis L, Nemeroff CB, Carlson GA, Joshi PT, Reiss D, Todd RD, Hellander M (2003) Depression and bipolar support alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in children and adolescents. J Am Acad Child Adolesc Psychiatry 42:1494–1503

    Article  PubMed  Google Scholar 

  • Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245

    Article  PubMed  CAS  Google Scholar 

  • Dwivedi Y, Mondal AC, Shukla PK, Rizavi HS, Lyons J (2004) Altered protein kinase a in brain of learned helpless rats: effects of acute and repeated stress. Biol Psychiatry 56:30–40

    Article  PubMed  CAS  Google Scholar 

  • Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW, Carmody T, Rintelmann J (1997) A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54:1031–1037

    PubMed  CAS  Google Scholar 

  • Flugge G, Van KM, Meyer H, Fuchs E (2003) Alpha2a- and alpha2c-adrenoceptor regulation in the brain: alpha2A changes persist after chronic stress. Eur J Neurosci 17:917–928

    Article  PubMed  CAS  Google Scholar 

  • Geller B, Cooper TB, Graham DL, Marsteller FA, Bryant DM (1990) Double-blind placebo-controlled study of nortriptyline in depressed adolescents using a “fixed plasma level” design. Psychopharmacol Bull 26:85–90

    PubMed  CAS  Google Scholar 

  • Geller B, Cooper TB, Graham DL, Fetner HH, Marsteller FA, Wells JM (1992) Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 6- to 12-year-olds with major depressive disorder. J Am Acad Child Adolesc Psychiatry 31:34–44

    Article  PubMed  CAS  Google Scholar 

  • Hajszan T, Dow A, Warner-Schmidt JL, Szigeti-Buck K, Sallam NL, Parducz A, Leranth C, Duman RS (2008) Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol Psychiatry 65(5):392–400

    Article  PubMed  Google Scholar 

  • Henn FA, Vollmayr B (2005) Stress models of depression: forming genetically vulnerable strains. Neurosci Biobehav Rev 29:799–804

    Article  PubMed  Google Scholar 

  • Jick H, Kaye JA, Jick SS (2004) Antidepressants and the risk of suicidal behaviors. JAMA 292:338–343

    Article  PubMed  CAS  Google Scholar 

  • Keenan-Miller D, Hammen CL, Brennan PA (2007) Health outcomes related to early adolescent depression. J Adolesc Health 41:256–262

    Article  PubMed  Google Scholar 

  • Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP, Birmaher B, Hagino OR, Koplewicz H, Carlson GA, Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar V, Papatheodorou G, Sack WH, Sweeney M, Wagner KD, Weller EB, Winters NC, Oakes R, McCafferty JP (2001) Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 40:762–772

    Article  PubMed  CAS  Google Scholar 

  • Kikuchi A, Shimizu K, Nibuya M, Hiramoto T, Kanda Y, Tanaka T, Watanabe Y, Takahashi Y, Nomura S (2008) Relationship between post-traumatic stress disorder-like behavior and reduction of hippocampal 5-bromo-2′-deoxyuridine-positive cells after inescapable shock in rats. Psychiatry Clin Neurosci 62(6):713–720

    Article  PubMed  Google Scholar 

  • King JA, Abend S, Edwards E (2001) Genetic predisposition and the development of posttraumatic stress disorder in an animal model. Biol Psychiatry 50(4):231–237

    Article  PubMed  CAS  Google Scholar 

  • Kovacs M, Goldston D, Gatsonis C (1993) Suicidal behaviors and childhood-onset depressive disorders: a longitudinal investigation. J Am Acad Child Adolesc Psychiatry 32:8–20

    Article  PubMed  CAS  Google Scholar 

  • Kozisek ME, Deupree JD, Burke WJ, Bylund DB (2007) Appropriate dosing regimens for treating juvenile rats with desipramine for neuropharmacological and behavioral studies. J Neurosci Methods 163:83–91

    Article  PubMed  CAS  Google Scholar 

  • Kratochvil CJ, Vitiello B, Walkup J, Emslie G, Waslick BD, Weller EB, Burke WJ, March JS (2006) Selective serotonin reuptake inhibitors in pediatric depression: is the balance between benefits and risks favorable? J Child Adolesc Psychopharmacol 16:11–24

    Article  PubMed  Google Scholar 

  • Kutcher S, Boulos C, Ward B, Marton P, Simeon J, Ferguson HB, Szalai J, Katic M, Roberts N, Dubois C (1994) Response to desipramine treatment in adolescent depression: a fixed-dose, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 33:686–694

    Article  PubMed  CAS  Google Scholar 

  • Kye CH, Waterman GS, Ryan ND, Birmaher B, Williamson DE, Iyengar S, Dachille S (1996) A randomized, controlled trial of amitriptyline in the acute treatment of adolescent major depression. J Am Acad Child Adolesc Psychiatry 35:1139–1144

    Article  PubMed  CAS  Google Scholar 

  • Lehmann J, Feldon J (2000) Long-term biobehavioral effects of maternal separation in the rat: consistent or confusing? Rev Neurosci 11:383–408

    PubMed  CAS  Google Scholar 

  • Leshner AI, Remler H, Biegon A, Samuel D (1979) Desmethylimipramine (DMI) counteracts learned helplessness in rats. Psychopharmacology (Berl) 66:207–208

    Article  CAS  Google Scholar 

  • Licinio J, Wong ML (2005) Depression, antidepressants and suicidality: a critical appraisal. Nat Rev Drug Discov 4:165–171

    Article  PubMed  CAS  Google Scholar 

  • Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RCS, Paul IA (2005) Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology 31:47–57

    Google Scholar 

  • Maier SF, Watkins LR (2005) Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotrophin-releasing factor. Neurosci Biobehav Rev 29:829–841

    Article  PubMed  CAS  Google Scholar 

  • Malberg JE, Duman RS (2003) Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28:1562–1571

    Article  PubMed  CAS  Google Scholar 

  • March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J (2004) Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA 292:807–820

    Article  PubMed  CAS  Google Scholar 

  • Martin P, Puech AJ (1996) Antagonism by benzodiazepines of the effects of serotonin-, but not norepinephrine-, uptake blockers in the learned helplessness paradigm in rats. Biol Psychiatry 39:882–890

    Article  PubMed  CAS  Google Scholar 

  • Martin P, Soubrie P, Simon P (1987) The effect of monoamine oxidase inhibitors compared with classical tricyclic antidepressants on learned helplessness paradigm. Prog Neuropsychopharmacol Biol Psychiatry 11:1–7

    Article  PubMed  CAS  Google Scholar 

  • Martin P, Soubrie P, Puech AJ (1990) Reversal of helpless behavior by serotonin uptake blockers in rats. Psychopharmacology (Berl) 101:403–407

    Article  CAS  Google Scholar 

  • Maudhuit C, Prevot E, Dangoumau L, Martin P, Hamon M, Adrien J (1997) Antidepressant treatment in helpless rats: effect on the electrophysiological activity of raphe dorsalis serotonergic neurons. Psychopharmacology (Berl) 130:269–275

    Article  CAS  Google Scholar 

  • Murrin LC, Sanders JD, Bylund DB (2007) Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adults. Biochem Pharmacol 73:1225–1236

    Article  PubMed  CAS  Google Scholar 

  • Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (1997) Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283:1305–1322

    PubMed  CAS  Google Scholar 

  • Pavcovich LA, Ramirez OA (1993) Effects of chronic desipramine administration on the locus coeruleus neuronal activity in the learned helplessness paradigm. Brain Res Bull 32:83–86

    Article  PubMed  CAS  Google Scholar 

  • Petti TA, Law W III (1982) Imipramine treatment of depressed children: a double-blind pilot study. J Clin Psychopharmacol 2:107–110

    PubMed  CAS  Google Scholar 

  • Petty F, Kramer G, Wilson L, Jordan S (1994) In vivo serotonin release and learned helplessness. Psychiatry Res 52:285–293

    Article  PubMed  CAS  Google Scholar 

  • Portfors CV (2007) Types and functions of ultrasonic vocalizations in laboratory rats and mice. J Am Assoc Lab Anim Sci 46:28–34

    PubMed  CAS  Google Scholar 

  • Reed AL, Happe HK, Petty F, Bylund DB (2008) Juvenile rats in the forced-swim test model the human response to antidepressant treatment for pediatric depression. Psychopharmacology (Berl) 197:433–441

    Article  CAS  Google Scholar 

  • Rodrigues-Filho R, Takahashi RN (1999) Antinociceptive effects induced by desipramine and fluoxetine are dissociated from their antidepressant or anxiolytic action in mice. Int J Neuropharmacol 2:262–269

    Google Scholar 

  • Seligman ME, Beagley G (1975) Learned helplessness in the rat. J Comp Physiol Psychol 88:534–541

    Article  PubMed  CAS  Google Scholar 

  • Sherman AD, Petty F (1980) Neurochemical basis of the action of antidepressants on learned helplessness. Behav Neural Biol 30:119–134

    Article  PubMed  CAS  Google Scholar 

  • Sherman AD, Allers GL, Petty F, Henn FA (1979) A neuropharmacologically-relevant animal model of depression. Neuropharmacology 18:891–893

    Article  PubMed  CAS  Google Scholar 

  • Sherman AD, Sacquitne JL, Petty F (1982) Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 16:449–454

    Article  PubMed  CAS  Google Scholar 

  • Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22:3251–3261

    PubMed  CAS  Google Scholar 

  • Suda S, Segi-Nishida E, Newton SS, Duman RS (2008) A postpartum model in rat: behavioral and gene expression changes induced by ovarian steroid deprivation. Biol Psychiatry 64:311–319

    Article  PubMed  CAS  Google Scholar 

  • Takamori K, Yoshida S, Okuyama S (2001) Availability of learned helplessness test as a model of depression compared to a forced swimming test in rats. Pharmacology 63:147–153

    Article  PubMed  CAS  Google Scholar 

  • Takase LF, Nogueira MI, Bland ST, Baratta M, Watkins LR, Maier SF, Fornal CA, Jacobs BL (2005) Effect of number of tailshocks on learned helplessness and activation of serotonergic and noradrenergic neurons in the rat. Behav Brain Res 162:299–306

    Article  PubMed  CAS  Google Scholar 

  • Thiebot MH, Martin P, Puech AJ (1992) Animal behavioural studies in the evaluation of antidepressant drugs. Br J Psychiatry Suppl 160(15):44–50

    Google Scholar 

  • Valuck RJ, Libby AM, Sills MR, Giese AA, Allen RR (2004) Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensity-adjusted retrospective cohort study. CNS Drugs 18:1119–1132

    Article  PubMed  CAS  Google Scholar 

  • Vollmayr B, Henn FA (2001) Learned helplessness in the rat: improvements in validity and reliability. Brain Res Brain Res Protoc 8:1–7

    Article  PubMed  CAS  Google Scholar 

  • Wagner HR, Hall TL, Cote IL (1977) The applicability of inescapable shock as a source of animal depression. J Gen Psychol 96:313–318

    PubMed  Google Scholar 

  • Willner P (1986) Validation criteria for animal models of human mental disorders: learned helplessness as a paradigm case. Prog Neuropsychopharmacol Biol Psychiatry 10:677–690

    Article  PubMed  CAS  Google Scholar 

  • Willner P (1990) Animal models of depression: an overview. Pharmacol Ther 45:425–455

    Article  PubMed  CAS  Google Scholar 

  • Wu J, Kramer GL, Kram M, Steciuk M, Crawford IL, Petty F (1999) Serotonin and learned helplessness: a regional study of 5-HT1A, 5-HT2A receptors and the serotonin transport site in rat brain. J Psychiatr Res 33:17–22

    Article  PubMed  CAS  Google Scholar 

  • Zazpe A, Artaiz I, Labeaga L, Lucero ML, Orjales A (2007) Reversal of learned helplessness by selective serotonin reuptake inhibitors in rats is not dependent on 5-HT availability. Neuropharmacology 52:975–984

    Article  PubMed  CAS  Google Scholar 

  • Zisook S, Lesser I, Stewart JW, Wisniewski SR, Balasubramani GK, Fava M, Gilmer WS, Dresselhaus TR, Thase ME, Nierenberg AA, Trivedi MH, Rush AJ (2007) Effect of age at onset on the course of major depressive disorder. Am J Psychiatry 164:1539–1546

    Article  PubMed  Google Scholar 

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Acknowledgments

This research was supported by a grant from the Mental Health Institute of the National Institutes of Health number MH66959 and a Creighton University Health Future Foundation internal grant. ALR was also in part supported by a fellowship from the Nebraska IDeA Networks of Biomedical Research Excellence (NE-INBRE), grant number P20 RR16469. All experiments comply with the current laws of the country in which they were performed.

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Authors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center, Omaha, NE, 68198-5800, USA

    Abbey L. Reed, Jeffrey C. Anderson & David B. Bylund

  2. Department of Psychiatry, Creighton University, 3528 Dodge Street, Omaha, NE, 68131, USA

    Frederick Petty, Hesham El Refaey & H. Kevin Happe

  3. Omaha Veterans Administration Medical Center, 4101 Woolworth Avenue, Omaha, NE, 68105, USA

    Frederick Petty & H. Kevin Happe

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  1. Abbey L. Reed
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  2. Jeffrey C. Anderson
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  3. David B. Bylund
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  4. Frederick Petty
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  5. Hesham El Refaey
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  6. H. Kevin Happe
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Correspondence to Abbey L. Reed.

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Reed, A.L., Anderson, J.C., Bylund, D.B. et al. Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats. Psychopharmacology 205, 249–259 (2009). https://doi.org/10.1007/s00213-009-1535-2

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  • DOI: https://doi.org/10.1007/s00213-009-1535-2

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