Skip to main content
Log in

Citalopram Protects Against Cold-Restraint Stress-Induced Activation of Brain-Derived Neurotrophic Factor and Expression of Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells in Rats

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

The present study evaluates the protective effect of citalopram against cold-restraint stress (CRS) paradigm. Rats were pretreated with citalopram (0.1, 1.0, and 10.0 mg/kg) acutely and repeatedly for 21 days before exposure to the CRS procedure. None of the doses of citalopram attenuated CRS-induced gastric ulcers in the acute study. In contrast, repeated pretreatment of citalopram at a dose level of 0.1 mg/kg attenuated the CRS-induced gastric ulcers. Citalopram (0.1 mg/kg) diminished CRS-induced increase in plasma corticosterone, but not plasma norepinephrine level in the chronic study indicating its effect on hypothalamic-pituitary-adrenal axis function. Repeated citalopram (0.1 mg/kg) pretreatment attenuated CRS-induced changes in serotonin turnover in the hippocampus and amygdala. Moreover, repeated pretreatment with citalopram (0.1 mg/kg) mitigated the CRS-induced increase in the expression of brain-derived neurotrophic factor (BDNF) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) in the hippocampus and amygdala. These results suggest that there is a region- and a dose-specific effect of citalopram on CRS-induced BDNF-NFκB activation. Therefore, citalopram showed antistress activity in the CRS model through changes in the stress-responsive pathways such as hypothalamic-pituitary-adrenal-axis and brain serotonergic system apart from decreasing the expression of BDNF and NFκB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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

Similar content being viewed by others

References

  • Barde YA (1989) Trophic factors and neuronal survival. Neuron 2:1525–1534

    Article  CAS  PubMed  Google Scholar 

  • Bergami M, Rimondini R, Santi S, Blum R, Gotz M, Canossa M (2008) Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proc Natl Acad Sci U S A 105:15570–15575

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bernd P (2008) The role of neurotrophins during early development. Gene Expr 14:241–250

    Article  PubMed  Google Scholar 

  • Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309

    Article  CAS  PubMed  Google Scholar 

  • Chou D, Huang CC, Hsu KS (2014) Brain-derived neurotrophic factor in the amygdala mediates susceptibility to fear conditioning. Exp Neurol 255C:19–29

    Article  Google Scholar 

  • Cumming P, Brown E, Damsma G, Fibiger H (1992) Formation and clearance of interstitial metabolites of dopamine and serotonin in the rat striatum: an in vivo microdialysis study. J Neurochem 59:1905–1914

    Article  CAS  PubMed  Google Scholar 

  • Czéh C, Perez-Cruz C, Fuchs E, Flügge G (2008) Chronic stress-induced cellular changes in the medial prefrontal cortex and their potential clinical implications: does hemisphere location matter? Behav Brain Res 190:1–13

    Article  PubMed  Google Scholar 

  • Dhabhar FS, McEwen BS (1996) Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol 156:2608–2615

    CAS  PubMed  Google Scholar 

  • Dhami KS, Churchward MA, Baker GB, Todd KG (2013) Fluoxetine and citalopram decrease microglial release of glutamate and D-serine to promote cortical neuronal viability following ischemic insult. Mol Cell Neurosci 56:365–374

    Article  CAS  PubMed  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127

    Article  CAS  PubMed  Google Scholar 

  • Eller T, Vasar V, Shlik J, Maron E (2008) Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 32:445–450

    Article  CAS  PubMed  Google Scholar 

  • Farooqui T, Farooqui AA (2011) Lipid-mediated oxidative stress and inflammation in the pathogenesis of Parkinson’s disease. Park Dis 2011:247467

    Google Scholar 

  • Fayard B, Loeffler S, Weis J, Vögelin E, Krüttgen A (2005) The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR but not to TrkA or TrkC. J Neurosci Res 80:18–28

    Article  CAS  PubMed  Google Scholar 

  • Feldman S, Conforti N, Melamed E (1987) Paraventricular nucleus serotonin mediates neurally stimulated adrenocortical secretion. Brain Res Bull 18:165–168

    Article  CAS  PubMed  Google Scholar 

  • Garabadu D, Shah A, Ahmad A, Joshi VB, Saxena B, Palit G, Krishnamurthy S (2011) Eugenol as an anti-stress agent: modulation of hypothalamic-pituitary-adrenal axis and brain monoaminergic systems in a rat model of stress. Stress 14:145–155

    CAS  PubMed  Google Scholar 

  • Gelfo F, Tirassa P, De Bartolo P, Croce N, Bernardini S, Caltagirone C, Petrosini L, Angelucci F (2012) NPY intraperitoneal injections produce antidepressant-like effects and down regulate BDNF in the rat hypothalamus. CNS Neurosci Ther 18:487–492

    Article  CAS  PubMed  Google Scholar 

  • George DN, Duffaud AM, Pothuizen HH, Haddon JE, Killcross S (2010) Lesions to the ventral, but not the dorsal, medial prefrontal cortex enhances latent inhibition. Eur J Neurosci 31:1474–1482

    Article  PubMed  Google Scholar 

  • Guo S, Som AT, Waeber C, Lo EH (2012) Vascular neuroprotection via TrkB- and Akt-dependent cell survival signaling. J Neurochem 123:58–64

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Haastrup E, Knorr U, Erikstrup C, Kessing LV, Ullum H (2012) No evidence for an anti-inflammatory effect of escitalopram intervention in healthy individuals with a family history of depression. J Neuroimmunol 243:69–72

    Article  CAS  PubMed  Google Scholar 

  • Hahn A, Lanzenberger R, Wadsak W, Spindelegger C, Moser U, Mien LK, Mitterhauser M, Kasper S (2010) Escitalopram enhances the association of serotonin-1A autoreceptors to heteroreceptors in anxiety disorders. J Neurosci 30:14482–14489

    Article  CAS  PubMed  Google Scholar 

  • Herman JP, Cullinan WE (1997) Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20:78–84

    Article  CAS  PubMed  Google Scholar 

  • Herman JP, Ostrander MM, Mueller NK, Figueiredo H (2005) Limbic system mechanisms of stress regulation: hypothalamo–pituitary–adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 29:1201–1213

    Article  CAS  PubMed  Google Scholar 

  • Hesketh S, Jessop DS, Hogg S, Harbuz MS (2005) Differential actions of acute and chronic citalopram on the rodent hypothalamic-pituitary-adrenal axis response to acute restraint stress. J Endocrinol 185:373–382

    Article  CAS  PubMed  Google Scholar 

  • Ichikawa J, Meltzer HY (2000) The effect of serotonin1A receptor agonism on antipsychotic drug-induced dopamine release in rat striatum and nucleus accumbens. Brain Res 858:252–263

    Article  CAS  PubMed  Google Scholar 

  • Inoue T, Tsuchiya K, Koyama T (1994) Regional changes in dopamine and serotonin activation with various intensities of physical and psychological stress in the rat brain. Pharmacol Biochem Behav 49:911–920

    Article  CAS  PubMed  Google Scholar 

  • Ishida-Tokuda K, Ohno Y, Sakamoto H, Ishibashi T, Wakabayashi J, Tojima R, Morita T, Nakamura M (1996) Evaluation of perospirone (SM-9018), a novel serotonin-2 and dopamine-2 receptor antagonist, and other antipsychotics in the conditioned fear stress-induced freezing behavior model in rats. Jpn J Pharmacol 72:119–126

    Article  CAS  PubMed  Google Scholar 

  • Jacobsen JP, Mørk A (2004) The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels. Brain Res 1024:183–192

    Article  CAS  PubMed  Google Scholar 

  • Kim C, Speisky MB, Kharouba SN (1987) Rapid and sensitive method for measuring norepinephrin, dopamine, 5-hydroxytryptamine and their major metabolites in rat brain by high performance liquid chromatography. J Chromatogr 386:25–35

    Article  CAS  PubMed  Google Scholar 

  • Koob GF (1999) Corticotropin-releasing factor, norepinephrine and stress. Biol Psychiatry 46:1176–1180

    Article  Google Scholar 

  • Krishnamurthy S, Garabadu D, Reddy NR, Joy KP (2011) Risperidone in ultra low dose protects against stress in the rodent cold restraint model by modulating stress pathways. Neurochem Res 36:1750–1758

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Garg R (2009) Protective effects of antidepressants against chronic fatigue syndrome-induced behavioral changes and biochemical alterations. Fundam Clin Pharmacol 23:89–95

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Garg R, Gaur V, Kumar P (2010) Possible role of NO modulators in protective effect of trazodone and citalopram (antidepressants) in acute immobilization stress in mice. Indian J Exp Biol 48:1131–1135

    CAS  PubMed  Google Scholar 

  • Kvetnanský R, Fukuhara K, Pacák K, Cizza G, Goldstein DS, Kopin IJ (1993) Endogenous glucocorticoids restrain catecholamine synthesis and release at rest and during immobilization stress in rats. Endocrinology 133:1411–1419

    PubMed  Google Scholar 

  • Liang B, Wei DL, Cheng YN, Yuan HJ, Lin J, Cui XZ, Luo MJ, Tan JH (2013) Restraint stress impairs oocyte developmental potential in mice: role of CRH-induced apoptosis of ovarian cells. Biol Reprod 89:64

    Article  PubMed  Google Scholar 

  • Lipsky RH, Marini AM (2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci 1122:130–143

    Article  CAS  PubMed  Google Scholar 

  • Lowry OH, Rosenborough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Lowry CA, Plant A, Shanks N, Ingram CD, Lightman SL (2003) Anatomical and functional evidence for a stress-responsive, monoamine-accumulating area in the dorsomedial hypothalamus of adult rat brain. Horm Behav 43:254–262

    Article  CAS  PubMed  Google Scholar 

  • Mahesh R, Pandey DK, Katiyar S, Kukade G, Viyogi S, Rudra A (2010) Effect of anti-depressants on neuro-behavioural consequences following impact accelerated traumatic brain injury in rats. Indian J Exp Biol 48:466–473

    CAS  PubMed  Google Scholar 

  • Moncek F, Duncko R, Jezova D (2003) Repeated citalopram treatment but not stress exposure attenuates hypothalamic-pituitary-adrenocortical axis response to acute citalopram injection. Life Sci 72:1353–1365

    Article  CAS  PubMed  Google Scholar 

  • Mönnikes H, Tebbe JJ, Hildebrandt M, Arck P, Osmanoglou E, Rose M, Klapp B, Wiedenmann B, Heymann-Mönnikes I (2001) Role of stress in functional gastrointestinal disorders: evidence for stress-induced alterations in gastrointestinal motility and sensitivity. Dig Dis 19:201–211

    Article  PubMed  Google Scholar 

  • Morilak DA, Barrera G, Echevarria J, Garcia AS, Hernandez A, Ma S, Petre CO (2005) Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry 29:1214–1224

    Article  CAS  PubMed  Google Scholar 

  • Nelson AJD, Thur KE, Marsden CA, Cassaday HJ (2010) Catecholaminergic depletion within the prelimbic medial prefrontal cortex enhances latent inhibition. Neuroscience 170:99–106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Okamoto H, Shino Y, Hashimoto K, Kumakiri C, Shimizu E, Shirasawa H, Iyo M (2003) Dynamic changes in AP-1 transcription factor DNA binding activity in rat brain following administration of antidepressant amitriptyline and brain-derived neurotrophic factor. Neuropharmacology 45(2):251–259

    Article  CAS  PubMed  Google Scholar 

  • Oxenkrug GF, Requintina PJ (1998) The effect of MAO-A inhibition and cold-immobilization stress on N-acetylserotonin and melatonin in SHR and WKY rats. J Neural Transm Suppl 52:333–336

    Article  CAS  PubMed  Google Scholar 

  • Palkovits M, Brownstein MJ (1988) Maps and guide to microdissection of the rat brain. Elsevier, New York

    Google Scholar 

  • Park SH, Choi SH, Lee J, Kang S, Shin YC, Kim HJ, Kim HJ, Shin SK, Lee MS, Shin KH (2008) Effects of repeated citalopram treatments on chronic mild stress-induced growth associated protein-43 mRNA expression in rat hippocampus. Korean J Physiol Pharmacol 12:117–123

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reichardt LF (2006) Neurotrophin-regulated signaling pathways. Philos Trans R Soc Lond B Biol Sci 361:1545–1564

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Retana-Marquez S, Salazar ED, Velazquez-Moctezuma J (1996) Effect of acute and chronic stress on masculine sexual behavior in the rat. Psychoneuroendocrinology 21:39–50

    Article  CAS  PubMed  Google Scholar 

  • Roux PP, Barker PA (2002) Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 67:203–233

    Article  CAS  PubMed  Google Scholar 

  • Sairam K, Priyambada S, Aryya NC, Goel RK (2003) Gastroduodenal ulcer protective activity of Asparagus racemosus: an experimental, biochemical and histological study. J Ethnopharmacol 86:1–10

    Article  CAS  PubMed  Google Scholar 

  • Sastre E, Nicolay A, Bruguerolle B, Portugal H (2004) Method for simultaneous measurement of norepinephrine, 3-methoxy-4-hydroxyphenylglycol and 3, 4-dihydroxyphenylglycol by liquid chromatography with electrochemical detection: application in rat cerebral cortex and plasma after lithium chloride treatment. J Chromatogr B Biomed Sci Appl 801:205–211

    CAS  Google Scholar 

  • Saxena B, Singh S (2011) Investigations on gastroprotective effect of citalopram, an antidepressant drug against stress and pyloric ligation induced ulcers. Pharmacol Rep 63:1413–1426

    Article  CAS  PubMed  Google Scholar 

  • Sheikh N, Ahmad A, Siripurapu KB, Kuchibhotla VK, Singh S, Palit G (2007) Effect of Bacopa monniera on stress induced changes in plasma corticosterone and brain monoamines in rats. J Ethnopharmacol 111:671–676

    Article  PubMed  Google Scholar 

  • Shi SS, Shao SH, Yuan BP, Pan F, Li ZL (2010) Acute stress and chronic stress change brain-derived neurotrophic factor (BDNF) and tyrosine kinase-coupled receptor (TrkB) expression in both young and aged rat hippocampus. Yonsei Med J 51:661–671

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Soll AH (1990) Pathogenesis of peptic ulcer and implications for therapy. N Engl J Med 322:909–916

    Article  CAS  PubMed  Google Scholar 

  • Southwick SM, Vythilingam M, Charney DS (2005) The psychobiology of depression and resilience to stress: implications for prevention and treatment. Annu Rev Clin Psychol 1:255–291

    Article  PubMed  Google Scholar 

  • Sudo N, Oyama N, Yu XN, Kub C (2001) Restraint stress-induced elevation of endogenous glucocorticoids decreases Peyer’s patch cell numbers via mechanisms that are either dependent or independent on apoptotic cell death. Neuroimmunomodulation 6:333–339

    Article  Google Scholar 

  • Sugama S (2009) Stress-induced microglial activation may facilitate the progression of neurodegenerative disorders. Med Hypotheses 73:1031–1034

    Article  CAS  PubMed  Google Scholar 

  • Taché Y, Martinez V, Million M, Wang L (2001) Stress and the gastrointestinal tract: III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors. Am J Physiol Gastrointest Liver Physiol 280:G173–G177

    PubMed  Google Scholar 

  • Tsai SF, Huang TY, Chang CY, Hsu YC, Chen SJ, Yu L, Kuo YM, Jen CJ (2014) Social instability stress differentially affects amygdalar neuron adaptations and memory performance in adolescent and adult rats. Front Behav Neurosci 8:27

    PubMed Central  PubMed  Google Scholar 

  • Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR (2012) A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun 26:469–479

    Article  CAS  PubMed  Google Scholar 

  • Woodward JH, Emery WP (1987) Determination of plasma corticosterone using high-performance liquid chromatography. J Chromatogr 419:280–284

    Article  CAS  PubMed  Google Scholar 

  • Xu H, Steven Richardson J, Li XM (2003) Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus. Neuropsychopharmacology 28(1):53–62

    Article  CAS  PubMed  Google Scholar 

  • Zhu D, Tong Q, Liu W, Tian M, Xie W, Ji L, Shi J (2014) Angiotensin (1–7) protects against stress-induced gastric lesions in rats. Biochem Pharmacol 87:467–476

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

BR is thankful to the University Grant Commission (UGC), India for the student fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sairam Krishnamurthy.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garabadu, D., Reddy, B.C.M.H. & Krishnamurthy, S. Citalopram Protects Against Cold-Restraint Stress-Induced Activation of Brain-Derived Neurotrophic Factor and Expression of Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells in Rats. J Mol Neurosci 55, 355–366 (2015). https://doi.org/10.1007/s12031-014-0334-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-014-0334-3

Keywords

Navigation