Skip to main content
SpringerLink
Log in

Effects of desipramine treatment on stress-induced up-regulation of norepinephrine transporter expression in rat brains

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

Abstract

Rationale

Many studies demonstrate down-regulation of the norepinephrine transporter (NET) by desipramine (DMI) in vitro and in stress-naive rats. Little is known regarding regulation of the NET in stressed animals.

Objective

The present study was designed to investigate effects of DMI on the expression of NET and protein kinases in the stress rat.

Methods

Adult Fischer 344 rats were subjected to chronic social defeat (CSD) for 4 weeks. DMI (10 mg/kg, intraperitoneal (i.p.)) was administered concurrently with CSD or 1 or 2 weeks after cessation of CSD. Sucrose consumption, NET expression, and protein kinases were measured.

Results

CSD significantly increased messenger RNA (mRNA) and protein levels of NET in the locus coeruleus, as well as NET protein levels in the hippocampus, frontal cortex, and amygdala. These effects were nearly abolished when DMI was administered concurrently with CSD. CSD-induced up-regulation of NET expression in the locus coeruleus, hippocampus, and amygdala lasted at least 2 weeks after cessation of CSD, an effect that was significantly attenuated by 1 or 2 weeks of DMI treatment starting from cessation of the CSD. Concurrent administration of DMI with CSD did not markedly interfere with CSD-induced decreases in protein levels of protein kinases A and C in these brain regions, but it did reverse the CSD-induced reduction in phosphorylated cAMP response element-binding (pCREB) protein levels in most brain regions.

Conclusion

These findings suggest that NET regulation by DMI occurs in both stressed and behaviorally naive rats, and DMI-induced changes in pCREB may be involved.

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Akin D, Manier DH, Sanders-Bush E, Shelton RC (2005) Signal transduction abnormalities in melancholic depression. Int J Neuropsychopharmacol 8:5–16

    Article  CAS  PubMed  Google Scholar 

  • Apparsundaram S, Galli A, DeFelice LJ, Hartzell HC, Blakely RD (1998) Acute regulation of norepinephrine transport: I. protein kinase C-linked muscarinic receptors influence transport capacity and transporter density in SK-N-SH cells. J Pharmacol Exp Ther 287:733–743

    CAS  PubMed  Google Scholar 

  • Barker E, Blakely R (1995) Norepinephrine and serotonin transporters. Molecular targets of antidepressant drugs. In: Bloom F, Kupfer D (eds) Psychopharmacology. A fourth generation of progress. Raven Press, New York, pp 321–333

    Google Scholar 

  • Bauer ME, Tejani-Butt SM (1992) Effects of repeated administration of desipramine or electroconvulsive shock on norepinephrine uptake sites measured by [3H]nisoxetine autoradiography. Brain Res 582:208–214

    Article  CAS  PubMed  Google Scholar 

  • Benmansour S, Altamirano AV, Jones DJ, Sanchez TA, Gould GG, Pardon MC, Morilak DA, Frazer A (2004) Regulation of the norepinephrine transporter by chronic administration of antidepressants. Biol Psychiatry 55:313–316

    Article  CAS  PubMed  Google Scholar 

  • 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 19:10494–10501

    CAS  PubMed  Google Scholar 

  • Biegon A (1986) Effect of chronic desipramine treatment on dihydroalprenolol, imipramine, and desipramine binding sites: a quantitative autoradiographic study in the rat brain. J Neurochem 47:77–80

    Article  CAS  PubMed  Google Scholar 

  • Chandley MJ, Ordway GA (2012) Noradrenergic dysfunction in depresson and suicide. In: Dwivedi Y (ed) The Neurobiological Basis of Suicide, Boca Raton (FL), CRC Press, Chapter 3

  • Cheetham SC, Viggers JA, Butler SA, Prow MR, Heal DJ (1996) [3H]nisoxetine—a radioligand for noradrenaline reuptake sites: correlation with inhibition of [3H]noradrenaline uptake and effect of DSP-4 lesioning and antidepressant treatments. Neuropharmacology 35:63–70

    Article  CAS  PubMed  Google Scholar 

  • Chen P, Fan Y, Li Y, Sun Z, Bissette G, Zhu MY (2012) Chronic social defeat up-regulates expression of norepinephrine transporter in rat brains. Neurochem Int 60:9–20

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dhabhar FS, McEwen BS, Spencer RL (1993) Stress response, adrenal steroid receptor levels and corticosteroid-binding globulin levels—a comparison between Sprague-Dawley, Fischer 344 and Lewis rats. Brain Res 616:89–98

    Article  CAS  PubMed  Google Scholar 

  • Dhabhar FS, Miller AH, McEwen BS, Spencer RL (1995) Differential activation of adrenal steroid receptors in neural and immune tissues of Sprague Dawley, Fischer 344, and Lewis rats. J Neuroimmunol 56:77–90

    Article  CAS  PubMed  Google Scholar 

  • Donati RJ, Rasenick MM (2005) Chronic antidepressant treatment prevents accumulation of gsalpha in cholesterol-rich, cytoskeletal-associated, plasma membrane domains (lipid rafts). Neuropsychopharmacology 30:1238–1245

    CAS  PubMed  Google Scholar 

  • Durand M, Aguerre S, Fernandez F, Edno L, Combourieu I, Mormede P, Chaouloff F (2000) Strain-dependent neurochemical and neuroendocrine effects of desipramine, but not fluoxetine or imipramine, in spontaneously hypertensive and Wistar-Kyoto rats. Neuropharmacology 39:2464–2477

    Article  CAS  PubMed  Google Scholar 

  • Dwivedi Y, Rizavi HS, Shukla PK et al (2004) Protein kinase A in postmortem brain of depressed suicide victims: altered expression of specific regulatory and catalytic subunits. Biol Psychiatry 55:234–243

    Article  CAS  PubMed  Google Scholar 

  • Erickson SL, Gandhi AR, Asafu-Adjei JK, Sampson AR, Miner L, Blakely RD, Sesack SR (2011) Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex. Int J Neuropsychopharmacol 14:1219–1232

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fan Y, Chen P, Li Y, Zhu MY (2013) Effects of chronic social defeat on expression of dopamine beta-hydroxylase in rat brains. Synapse 67:300–312

    Article  CAS  PubMed  Google Scholar 

  • Fan Y, Huang J, Duffourc M, Kao RL, Ordway GA, Huang R, Zhu MY (2011) Transcription factor Phox2 upregulates expression of norepinephrine transporter and dopamine beta-hydroxylase in adult rat brains. Neuroscience 192:37–53

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fisar Z, Anders M, Tvrzicka E, Stankova B (2005) Effect of long-term administration of antidepressants on the lipid composition of brain plasma membranes. Gen Physiol Biophys 24:221–236

    CAS  PubMed  Google Scholar 

  • Guitart X, Kogan JH, Berhow M, Terwilliger RZ, Aghajanian GK, Nestler EJ (1993) Lewis and Fischer rat strains display differences in biochemical, electrophysiological and behavioral parameters: studies in the nucleus accumbens and locus coeruleus of drug naive and morphine-treated animals. Brain Res 611:7–17

    Article  CAS  PubMed  Google Scholar 

  • Hebert C, Habimana A, Elie R, Reader TA (2001) Effects of chronic antidepressant treatments on 5-HT and NA transporters in rat brain: an autoradiographic study. Neurochem Int 38:63–74

    Article  CAS  PubMed  Google Scholar 

  • Iversen LL (1971) Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmacol 41:571–591

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jang CG, Lee SY, Lee HK, Suh HW, Song DK (2002) Time courses of pCREB expression after dopaminergic stimulation by apomorphine in mouse brain. Arch Pharm Res 25:370–374

    Article  CAS  PubMed  Google Scholar 

  • Jeannotte AM, McCarthy JG, Redei EE, Sidhu A (2009) Desipramine modulation of alpha-, gamma-synuclein, and the norepinephrine transporter in an animal model of depression. Neuropsychopharmacology 34:987–998

    Article  CAS  PubMed  Google Scholar 

  • Jongen-Relo AL, Pothuizen HH, Feldon J, Pryce CR (2002) Comparison of central corticosteroid receptor expression in male Lewis and Fischer rats. Brain Res 953:223–231

    Article  CAS  PubMed  Google Scholar 

  • Kosten TA, Ambrosio E (2002) HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats. Psychoneuroendocrinology 27:35–69

    Article  CAS  PubMed  Google Scholar 

  • Krishnan V, Nestler EJ (2010) Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 167:1305–1320

    Article  PubMed Central  PubMed  Google Scholar 

  • Lacroix D, Blier P, Curet O, de Montigny C (1991) Effects of long-term desipramine administration on noradrenergic neurotransmission: electrophysiological studies in the rat brain. J Pharmacol Exp Ther 257:1081–1090

    CAS  PubMed  Google Scholar 

  • Lee CM, Javitch JA, Snyder SH (1983) Recognition sites for norepinephrine uptake: regulation by neurotransmitter. Science 220:626–629

    Article  CAS  PubMed  Google Scholar 

  • Lee SJ, Campomanes CR, Sikat PT, Greenfield AT, Allen PB, McEwen BS (2004) Estrogen induces phosphorylation of cyclic AMP response element binding (pCREB) in primary hippocampal cells in a time-dependent manner. Neuroscience 124:549–560

    Article  CAS  PubMed  Google Scholar 

  • Lenox RH, Frazer A (2002) Mechanism of action of antidepressants and mood stabilizers. In: Davis KL, Charney DS, Coyle JT, Nemeroff CB (eds) Neuropsychopharmacology. The Fifth Generation of Progress. Lippincott Williams and Wilkins, Philadelphia, pp 1139–1163

    Google Scholar 

  • Lopez-Rubalcava C, Lucki I (2000) Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test. Neuropsychopharmacology 22:191–199

    Article  CAS  PubMed  Google Scholar 

  • Mandela P, Ordway GA (2006) The norepinephrine transporter and its regulation. J Neurochem 97:310–333

    Article  CAS  PubMed  Google Scholar 

  • Mato S, Vidal R, Castro E, Diaz A, Pazos A, Valdizan EM (2010) Long-term fluoxetine treatment modulates cannabinoid type 1 receptor-mediated inhibition of adenylyl cyclase in the rat prefrontal cortex through 5-hydroxytryptamine 1A receptor-dependent mechanisms. Mol Pharmacol 77:424–434

    Article  CAS  PubMed  Google Scholar 

  • Nemeroff CB (2007) Prevalence and management of treatment-resistant depression. J Clin Psychiatry 68(Suppl 8):17–25

    CAS  PubMed  Google Scholar 

  • Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16:2365–2372

    CAS  PubMed  Google Scholar 

  • O’Leary OF, Bechtholt AJ, Crowley JJ, Hill TE, Page ME, Lucki I (2007) Depletion of serotonin and catecholamines block the acute behaviorial response to different classes of antidepressant drugs in the mouse tail suspension test. Psychopharmacology (Berl) 192:357-371

  • Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350:350–354

    Article  CAS  PubMed  Google Scholar 

  • Pandey GN, Dwivedi Y, Pandey SC, Conley RR, Roberts RC, Tamminga CA (1997) Protein kinase C in the postmortem brain of teenage suicide victims. Neurosci Lett 228:111–114

    Article  CAS  PubMed  Google Scholar 

  • Papp M, Willner P, Muscat R (1991) An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology (Berl) 104:255–259

    Article  CAS  Google Scholar 

  • Perez J, Tardito D, Racagni G, Smeraldi E, Zanardi R (2001) Protein kinase A and Rap1 levels in platelets of untreated patients with major depression. Mol Psychiatry 6:44–49

    Article  CAS  PubMed  Google Scholar 

  • Porterfield VM, Zimomra ZR, Caldwell EA, Camp RM, Gabella KM, Johnson JD (2011) Rat strain differences in restraint stress-induced brain cytokines. Neuroscience 188:48–54

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Racagni G, Mocchetti I, Calderini G, Battistella A, Brunello N (1983) Temporal sequence of changes in central noradrenergic system of rat after prolonged antidepressant treatment: receptor desensitization and neurotransmitter interactions. Neuropharmacology 22:415–424

    Article  CAS  PubMed  Google Scholar 

  • Rygula R, Abumaria N, Flugge G, Fuchs E, Ruther E, Havemann-Reinecke U (2005) Anhedonia and motivational deficits in rats: impact of chronic social stress. Behav Brain Res 162:127–134

    Article  PubMed  Google Scholar 

  • Sairanen M, O’Leary OF, Knuuttila JE, Castren E (2007) Chronic antidepressant treatment selectively increases expression of plasticity-related proteins in the hippocampus and medial prefrontal cortex of the rat. Neuroscience 144:368–374

    Article  CAS  PubMed  Google Scholar 

  • Santos JS, Lee DK, Ramamoorthy A (2004) Effects of antidepressants on the conformation of phospholipid headgroups studied by solid-state NMR. Magn Reson Chem 42:105–114

    Article  CAS  PubMed  Google Scholar 

  • Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861

    Article  CAS  PubMed  Google Scholar 

  • Shores MM, Szot P, Veith RC (1994) Desipramine-induced increase in norepinephrine transporter mRNA is not mediated via alpha 2 receptors. Brain Res Mol Brain Res 27:337–341

    Article  CAS  PubMed  Google Scholar 

  • Song L, Kitayama T, Morita K, Morioka N, Dohi T (2008) Down-regulation of norepinephrine transporter expression on membrane surface induced by chronic administration of desipramine and the antagonism by co-administration of local anesthetics in mice. Neurochem Int 52:826–833

    Article  CAS  PubMed  Google Scholar 

  • Sulser F (2002) The role of CREB and other transcription factors in the pharmacotherapy and etiology of depression. Ann Med 34:348–356

    Article  CAS  PubMed  Google Scholar 

  • Szot P, Ashliegh EA, Kohen R, Petrie E, Dorsa DM, Veith R (1993) Norepinephrine transporter mRNA is elevated in the locus coeruleus following short- and long-term desipramine treatment. Brain Res 618:308–312

    Article  CAS  PubMed  Google Scholar 

  • Tejani-Butt S, Kluczynski J, Pare WP (2003) Strain-dependent modification of behavior following antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry 27:7–14

    Article  CAS  PubMed  Google Scholar 

  • Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S, Storm D, Duman RS (2000) cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 20:4030–4036

    CAS  PubMed  Google Scholar 

  • Tiraboschi E, Tardito D, Kasahara J, Moraschi S, Pruneri P, Gennarelli M, Racagni G, Popoli M (2004) Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology 29:1831–1840

    Article  CAS  PubMed  Google Scholar 

  • Uchida S, Nishida A, Hara K et al (2008) Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor. Eur J Neurosci 27:2250–2261

    Article  PubMed  Google Scholar 

  • Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 93:358–364

    Article  CAS  Google Scholar 

  • Zhang J, Fan Y, Li Y, Zhu H, Wang L, Zhu MY (2012) Chronic social defeat up-regulates expression of the serotonin transporter in rat dorsal raphe nucleus and projection regions in a glucocorticoid-dependent manner. J Neurochem 123:1054–1068

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao Z, Baros AM, Zhang HT, Lapiz MD, Bondi CO, Morilak DA, O’Donnell JM (2008) Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine. Neuropsychopharmacology 33:3190–3200

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhu MY, Blakely RD, Apparsundaram S, Ordway GA (1998) Down-regulation of the human norepinephrine transporter in intact 293-hNET cells exposed to desipramine. J Neurochem 70:1547–1555

    Article  CAS  PubMed  Google Scholar 

  • Zhu MY, Kim CH, Hwang DY, Baldessarini RJ, Kim KS (2002) Effects of desipramine treatment on norepinephrine transporter gene expression in the cultured SK-N-BE(2)M17 cells and rat brain tissue. J Neurochem 82:146–153

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by NIH grant MH080323 and NARSAD Young Investigator Award. The authors thank Mr. Hobart Zhu for his helpful comments on the manuscript. The authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Departments of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37604, USA

    Yan Fan, Ping Chen, Ying Li, Gregory A. Ordway & Meng-Yang Zhu

  2. Department of Biochemistry and Molecular Biology, University of Nantong College of Medicine, Nantong, China

    Yan Fan

  3. School of Life Science and Technology, Tongji University, Shanghai, China

    Ping Chen

Authors
  1. Yan Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gregory A. Ordway
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meng-Yang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meng-Yang Zhu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fan, Y., Chen, P., Li, Y. et al. Effects of desipramine treatment on stress-induced up-regulation of norepinephrine transporter expression in rat brains. Psychopharmacology 232, 379–390 (2015). https://doi.org/10.1007/s00213-014-3674-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3674-3

Keywords

Search

Navigation