Skip to main content
Springer Nature Link
Log in

Adolescent Fluoxetine Exposure Induces Persistent Gene Expression Changes in the Hippocampus of Adult Male C57BL/6 Mice

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Mood-related disorders have a high prevalence among children and adolescents, posing a public health challenge, given their adverse impact on these young populations. Treatment with the selective serotonin reuptake inhibitor fluoxetine (FLX) is the first line of pharmacological intervention in pediatric patients suffering from affect-related illnesses. Although the use of this antidepressant has been deemed efficacious in the juvenile population, the enduring neurobiological consequences of adolescent FLX exposure are not well understood. Therefore, we explored for persistent molecular adaptations, in the adult hippocampus, as a function of adolescent FLX pretreatment. To do this, we administered FLX (20 mg/kg/day) to male C57BL/6 mice during adolescence (postnatal day [PD] 35–49). After a 21-day washout period (PD70), whole hippocampal tissue was dissected. We then used qPCR analysis to assess changes in the expression of genes associated with major intracellular signal transduction pathways, including the extracellular signal-regulated kinase (ERK), the phosphatidylinositide-3-kinase (PI3K)/AKT pathway, and the wingless (Wnt)-dishevelled-GSK3β signaling cascade. Our results show that FLX treatment results in long-term dysregulation of mRNA levels across numerous genes from the ERK, PI3K/AKT, and Wnt intracellular signaling pathways, along with increases of the transcription factors CREB, ΔFosB, and Zif268. Lastly, FLX treatment resulted in persistent increases of transcripts associated with cytoskeletal integrity (β-actin) and caspase activation (DIABLO), while decreasing genes associated with metabolism (fucose kinase) and overall neuronal activation (c-Fos). Collectively, these data indicate that adolescent FLX exposure mediates persistent alterations in hippocampal gene expression in adulthood, thus questioning the safety of early-life exposure to this antidepressant medication.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

Data Availability

All of the data that was generated and analyzed in this study are included in this article.

References

  1. Kessler RC, Bromet EJ (2013) The epidemiology of depression across cultures. Annu Rev Public Health 34:119–138. https://doi.org/10.1146/annurev-publhealth-031912-114409

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bandelow B, Michaelis S (2015) Epidemiology of anxiety disorders in the 21st century. Dialogues Clin Neurosci 17(3):327–335

    Article  Google Scholar 

  3. Birmaher B, Axelson DA, Monk K, Kalas C, Clark DB, Ehmann M, Bridge J, Heo J et al (2003) Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 42(4):415–423. https://doi.org/10.1097/01.CHI.0000037049.04952.9F

    Article  PubMed  Google Scholar 

  4. Merikangas KR, He JP, Burstein M, Swanson SA, Avenevoli S, Cui L, Benjet C, Georgiades K et al (2010) Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication--Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry 49(10):980–989. https://doi.org/10.1016/j.jaac.2010.05.017

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pine DS, Cohen P, Gurley D, Brook J, Ma Y (1998) The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry 55(1):56–64. https://doi.org/10.1001/archpsyc.55.1.56

    Article  CAS  PubMed  Google Scholar 

  6. Thapar A, Collishaw S, Potter R, Thapar AK (2010) Managing and preventing depression in adolescents. BMJ 340:c209. https://doi.org/10.1136/bmj.c209

    Article  PubMed  Google Scholar 

  7. Tiller JW (2013) Depression and anxiety. Med J Aust 199(S6):S28–S31

    Article  Google Scholar 

  8. Wehry AM, Beesdo-Baum K, Hennelly MM, Connolly SD, Strawn JR (2015) Assessment and treatment of anxiety disorders in children and adolescents. Curr Psychiatry Rep 17(7):52. https://doi.org/10.1007/s11920-015-0591-z

    Article  PubMed  Google Scholar 

  9. Bylund DB, Reed AL (2007) Childhood and adolescent depression: why do children and adults respond differently to antidepressant drugs? Neurochem Int 51(5):246–253

    Article  CAS  Google Scholar 

  10. Perez-Caballero L, Torres-Sanchez S, Bravo L, Mico JA, Berrocoso E (2014) Fluoxetine: a case history of its discovery and preclinical development. Expert Opin Drug Discovery 9(5):567–578. https://doi.org/10.1517/17460441.2014.907790

    Article  CAS  Google Scholar 

  11. Jane Garland JE, Kutcher S, Virani A, Elbe D (2016) Update on the use of SSRIs and SNRIs with children and adolescents in clinical practice. J Can Acad Child Adolesc Psychiatry 25(1):4–10

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA (2007) Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 297(15):1683–1696. https://doi.org/10.1001/jama.297.15.1683

    Article  CAS  PubMed  Google Scholar 

  13. Kronenberg S, Apter A, Brent D, Schirman S, Melhem N, Pick N, Gothelf D, Carmel M et al (2007) Serotonin transporter polymorphism (5-HTTLPR) and citalopram effectiveness and side effects in children with depression and/or anxiety disorders. J Child Adolesc Psychopharmacol 17(6):741–750. https://doi.org/10.1089/cap.2006.0144

    Article  PubMed  Google Scholar 

  14. Bowman MA, Daws LC (2019) Targeting serotonin transporters in the treatment of juvenile and adolescent depression. Front Neurosci 13:156. https://doi.org/10.3389/fnins.2019.00156

    Article  PubMed  PubMed Central  Google Scholar 

  15. Konrad K, Firk C, Uhlhaas PJ (2013) Brain development during adolescence: neuroscientific insights into this developmental period. Deutsches Arzteblatt Int 110(25):425–431. https://doi.org/10.3238/arztebl.2013.0425

    Article  Google Scholar 

  16. Alcantara LF, Warren BL, Parise EM, Iñiguez SD, Bolaños-Guzman CA (2014) Effects of psychotropic drugs on second messenger signaling and preference for nicotine in juvenile male mice. Psychopharmacology 231(8):1479–1492. https://doi.org/10.1007/s00213-014-3434-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Olivier JD, Blom T, Arentsen T, Homberg JR (2011) The age-dependent effects of selective serotonin reuptake inhibitors in humans and rodents: a review. Prog Neuro-Psychopharmacol Biol Psychiatry 35(6):1400–1408. https://doi.org/10.1016/j.pnpbp.2010.09.013

    Article  CAS  Google Scholar 

  18. Garcia-Carachure I, Flores-Ramirez FJ, Castillo SA, Themann A, Arenivar MA, Preciado-Pina J, Zavala AR, Lobo MK et al (2020) Enduring effects of adolescent ketamine exposure on cocaine- and sucrose-induced reward in male and female C57BL/6 mice. Neuropsychopharmacology. https://doi.org/10.1038/s41386-020-0654-7

  19. Sass A, Wortwein G (2012) The effect of subchronic fluoxetine treatment on learning and memory in adolescent rats. Behav Brain Res 228(1):169–175. https://doi.org/10.1016/j.bbr.2011.12.006

    Article  CAS  PubMed  Google Scholar 

  20. Flores-Ramirez FJ, Parise LF, Alipio JB, Garcia-Carachure I, Castillo SA, Rodriguez M, Themman A, Lira O et al (2019) Adolescent fluoxetine history impairs spatial memory in adult male, but not female, C57BL/6 mice. J Affect Disord 249:347–356. https://doi.org/10.1016/j.jad.2019.02.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Iñiguez SD, Riggs LM, Nieto SJ, Wright KN, Zamora NN, Cruz B, Zavala AR, Robison AJ et al (2015) Fluoxetine exposure during adolescence increases preference for cocaine in adulthood. Sci Rep 5:15009. https://doi.org/10.1038/srep15009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Flores-Ramirez FJ, Garcia-Carachure I, Sanchez DO, Gonzalez C, Castillo SA, Arenivar MA, Themann A, Lira O et al (2018) Fluoxetine exposure in adolescent and adult female mice decreases cocaine and sucrose preference later in life. J Psychopharmacol 269881118805488. https://doi.org/10.1177/0269881118805488

  23. Iñiguez SD, Warren BL, Bolaños-Guzmán CA (2010) Short- and long-term functional consequences of fluoxetine exposure during adolescence in male rats. Biol Psychiatry 67(11):1057–1066. https://doi.org/10.1016/j.biopsych.2009.12.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Iñiguez SD, Alcantara LF, Warren BL, Riggs LM, Parise EM, Vialou V, Wright KN, Dayrit G et al (2014) Fluoxetine exposure during adolescence alters responses to aversive stimuli in adulthood. J Neurosci 34(3):1007–1021. https://doi.org/10.1523/JNEUROSCI.5725-12.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Karpova NN, Lindholm J, Pruunsild P, Timmusk T, Castren E (2009) Long-lasting behavioural and molecular alterations induced by early postnatal fluoxetine exposure are restored by chronic fluoxetine treatment in adult mice. Eur Neuropsychopharmacol 19(2):97–108. https://doi.org/10.1016/j.euroneuro.2008.09.002

    Article  CAS  PubMed  Google Scholar 

  26. Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K (2007) High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317(5839):819–823. https://doi.org/10.1126/science.1144400

    Article  CAS  PubMed  Google Scholar 

  27. Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA et al (2006) Medication augmentation after the failure of SSRIs for depression. N Engl J Med 354(12):1243–1252. https://doi.org/10.1056/NEJMoa052964

    Article  CAS  PubMed  Google Scholar 

  28. Kroeze Y, Peeters D, Boulle F, Pawluski JL, van den Hove DL, van Bokhoven H, Zhou H, Homberg JR (2015) Long-term consequences of chronic fluoxetine exposure on the expression of myelination-related genes in the rat hippocampus. Transl Psychiatry 5:e642. https://doi.org/10.1038/tp.2015.145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59(12):1116–1127

    Article  CAS  Google Scholar 

  30. Freitas AE, Machado DG, Budni J, Neis VB, Balen GO, Lopes MW, de Souza LF, Dafre AL et al (2013) Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice. Behav Brain Res 237:176–184. https://doi.org/10.1016/j.bbr.2012.09.035

    Article  CAS  PubMed  Google Scholar 

  31. Bjorkholm C, Monteggia LM (2016) BDNF - a key transducer of antidepressant effects. Neuropharmacology 102:72–79. https://doi.org/10.1016/j.neuropharm.2015.10.034

    Article  CAS  PubMed  Google Scholar 

  32. Zhou WJ, Xu N, Kong L, Sun SC, Xu XF, Jia MZ, Wang Y, Chen ZY (2016) The antidepressant roles of Wnt2 and Wnt3 in stress-induced depression-like behaviors. Transl Psychiatry 6(9):e892. https://doi.org/10.1038/tp.2016.122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cha J, Greenberg T, Song I, Blair Simpson H, Posner J, Mujica-Parodi LR (2016) Abnormal hippocampal structure and function in clinical anxiety and comorbid depression. Hippocampus 26(5):545–553. https://doi.org/10.1002/hipo.22566

    Article  PubMed  PubMed Central  Google Scholar 

  34. Persson A, Sim SC, Virding S, Onishchenko N, Schulte G, Ingelman-Sundberg M (2014) Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Mol Psychiatry 19(6):733–741. https://doi.org/10.1038/mp.2013.89

    Article  CAS  PubMed  Google Scholar 

  35. Meyers RA, Zavala AR, Speer CM, Neisewander JL (2006) Dorsal hippocampus inhibition disrupts acquisition and expression, but not consolidation, of cocaine conditioned place preference. Behav Neurosci 120(2):401–412. https://doi.org/10.1037/0735-7044.120.2.401

    Article  CAS  PubMed  Google Scholar 

  36. Hitchcock LN, Lattal KM (2018) Involvement of the dorsal hippocampus in expression and extinction of cocaine-induced conditioned place preference. Hippocampus 28(3):226–238. https://doi.org/10.1002/hipo.22826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dale E, Pehrson AL, Jeyarajah T, Li Y, Leiser SC, Smagin G, Olsen CK, Sanchez C (2016) Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function. CNS Spectr 21(2):143–161. https://doi.org/10.1017/S1092852915000425

    Article  PubMed  Google Scholar 

  38. Duric V, Banasr M, Licznerski P, Schmidt HD, Stockmeier CA, Simen AA, Newton SS, Duman RS (2010) A negative regulator of MAP kinase causes depressive behavior. Nat Med 16(11):1328–1332. https://doi.org/10.1038/nm.2219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Council NR (2003) Guidelines for the care and use of mammals in neuroscience and behavioral research. National Academy Press, Washington

    Google Scholar 

  40. Andersen SL (2003) Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev 27(1-2):3–18. https://doi.org/10.1016/s0149-7634(03)00005-8

    Article  PubMed  Google Scholar 

  41. Abreu-Villaca Y, Filgueiras CC, Guthierrez M, Medeiros AH, Mattos MA, Pereira Mdos S, Manhaes AC, Kubrusly RC (2010) Exposure to tobacco smoke containing either high or low levels of nicotine during adolescence: differential effects on choline uptake in the cerebral cortex and hippocampus. Nicotine Tob Res 12(7):776–780. https://doi.org/10.1093/ntq075

    Article  CAS  PubMed  Google Scholar 

  42. Englander MT, Dulawa SC, Bhansali P, Schmauss C (2005) How stress and fluoxetine modulate serotonin 2C receptor pre-mRNA editing. J Neurosci 25(3):648–651

    Article  CAS  Google Scholar 

  43. LaPlant Q, Vialou V, Covington HE 3rd, Dumitriu D, Feng J, Warren BL, Maze I, Dietz DM et al (2010) Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci 13(9):1137–1143. https://doi.org/10.1038/nn.2619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C, Palme R, Griebel G et al (2011) Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry 16(12):1177–1188. https://doi.org/10.1038/mp.2011.48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Iñiguez SD, Charntikov S, Baella SA, Herbert MS, Bolaños-Guzmán CA, Crawford CA (2012) Post-training cocaine exposure facilitates spatial memory consolidation in c57bl/6 mice. Hippocampus 22(4):802–813. https://doi.org/10.1002/hipo.20941

    Article  CAS  PubMed  Google Scholar 

  46. Vialou V, Robison AJ, Laplant QC, Covington HE 3rd, Dietz DM, Ohnishi YN, Mouzon E, Rush AJ 3rd et al (2010) DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci 13(6):745–752. https://doi.org/10.1038/nn.2551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Meyers RA, Zavala AR, Neisewander JL (2003) Dorsal, but not ventral, hippocampal lesions disrupt cocaine place conditioning. Neuroreport 14(16):2127–2131. https://doi.org/10.1097/01.wnr.0000095709.83808.81

    Article  PubMed  Google Scholar 

  48. Castren E, Rantamaki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 70(5):289–297. https://doi.org/10.1002/dneu.20758

    Article  CAS  PubMed  Google Scholar 

  49. Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64(2):238–258. https://doi.org/10.1124/pr.111.005108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Warren BL, Iñiguez SD, Alcantara LF, Wright KN, Parise EM, Weakley SK, Bolanos-Guzman CA (2011) Juvenile administration of concomitant methylphenidate and fluoxetine alters behavioral reactivity to reward- and mood-related stimuli and disrupts ventral tegmental area gene expression in adulthood. J Neurosci 31(28):10347–10358. https://doi.org/10.1523/JNEUROSCI.1470-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yan L, Xu X, He Z, Wang S, Zhao L, Qiu J, Wang D, Gong Z et al (2020) Antidepressant-like effects and cognitive enhancement of coadministration of Chaihu Shugan San and fluoxetine: dependent on the BDNF-ERK-CREB signaling pathway in the hippocampus and frontal cortex. Biomed Res Int 2020:2794263. https://doi.org/10.1155/2020/2794263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Homberg JR, Olivier JD, Blom T, Arentsen T, van Brunschot C, Schipper P, Korte-Bouws G, van Luijtelaar G et al (2011) Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat. PLoS One 6(1):e16646. https://doi.org/10.1371/journal.pone.0016646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tropea TF, Kosofsky BE, Rajadhyaksha AM (2008) Enhanced CREB and DARPP-32 phosphorylation in the nucleus accumbens and CREB, ERK, and GluR1 phosphorylation in the dorsal hippocampus is associated with cocaine-conditioned place preference behavior. J Neurochem 106(4):1780–1790. https://doi.org/10.1111/j.1471-4159.2008.05518.x

    Article  CAS  PubMed  Google Scholar 

  54. Hearing MC, Schochet TL, See RE, McGinty JF (2010) Context-driven cocaine-seeking in abstinent rats increases activity-regulated gene expression in the basolateral amygdala and dorsal hippocampus differentially following short and long periods of abstinence. Neuroscience 170(2):570–579. https://doi.org/10.1016/j.neuroscience.2010.07.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gajewski PA, Eagle AL, Williams ES, Manning CE, Lynch H, McCornack C, Maze I, Heller EA et al (2019) Epigenetic regulation of hippocampal Fosb expression controls behavioral responses to cocaine. J Neurosci 39(42):8305–8314. https://doi.org/10.1523/JNEUROSCI.0800-19.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Fosnocht AQ, Lucerne KE, Ellis AS, Olimpo NA, Briand LA (2019) Adolescent social isolation increases cocaine seeking in male and female mice. Behav Brain Res 359:589–596. https://doi.org/10.1016/j.bbr.2018.10.007

    Article  CAS  PubMed  Google Scholar 

  57. McLaughlin JP, Li S, Valdez J, Chavkin TA, Chavkin C (2006) Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system. Neuropsychopharmacology 31(6):1241–1248. https://doi.org/10.1038/sj.npp.1300872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Iñiguez SD, Parise LF, Lobo MK, Flores-Ramirez FJ, Garcia-Carachure I, Warren BL, Robison AJ (2019) Upregulation of hippocampal extracellular signal-regulated kinase (ERK)-2 induces antidepressant-like behavior in the rat forced swim test. Behav Neurosci 133(2):225–231. https://doi.org/10.1037/bne0000303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Martin ED, Sanchez-Perez A, Trejo JL, Martin-Aldana JA, Cano Jaimez M, Pons S, Acosta Umanzor C, Menes L et al (2012) IRS-2 Deficiency impairs NMDA receptor-dependent long-term potentiation. Cereb Cortex 22(8):1717–1727. https://doi.org/10.1093/cercor/bhr216

    Article  PubMed  Google Scholar 

  60. Russo SJ, Bolaños CA, Theobald DE, DeCarolis NA, Renthal W, Kumar A, Winstanley CA, Renthal NE et al (2007) IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Nat Neurosci 10(1):93–99. https://doi.org/10.1038/nn1812

    Article  CAS  PubMed  Google Scholar 

  61. Iñiguez SD, Warren BL, Neve RL, Nestler EJ, Russo SJ, Bolaños-Guzmán CA (2008) Insulin receptor substrate-2 in the ventral tegmental area regulates behavioral responses to cocaine. Behav Neurosci 122(5):1172–1177. https://doi.org/10.1037/a0012893

    Article  PubMed  PubMed Central  Google Scholar 

  62. Glombik K, Slusarczyk J, Trojan E, Chamera K, Budziszewska B, Lason W, Basta-Kaim A (2017) Regulation of insulin receptor phosphorylation in the brains of prenatally stressed rats: new insight into the benefits of antidepressant drug treatment. Eur Neuropsychopharmacol 27(2):120–131. https://doi.org/10.1016/j.euroneuro.2016.12.005

    Article  CAS  PubMed  Google Scholar 

  63. Krishnan V, Han MH, Mazei-Robison M, Iñiguez SD, Ables JL, Vialou V, Berton O, Ghose S et al (2008) AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli. Biol Psychiatry 64(8):691–700. https://doi.org/10.1016/j.biopsych.2008.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wilkinson MB, Dias C, Magida J, Mazei-Robison M, Lobo M, Kennedy P, Dietz D, Covington H 3rd et al (2011) A novel role of the WNT-dishevelled-GSK3beta signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci 31(25):9084–9092. https://doi.org/10.1523/JNEUROSCI.0039-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dias C, Dietz D, Mazei-Robison M, Sun H, Damez-Werno D, Ferguson D, Wilkinson M, Magida J et al (2015) Dishevelled-2 regulates cocaine-induced structural plasticity and Rac1 activity in the nucleus accumbens. Neurosci Lett 598:23–28. https://doi.org/10.1016/j.neulet.2015.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Abdolmaleki F, Ahmadpour-Yazdi H, Hayat SMG, Gheibi N, Johnston TP, Sahebkar A (2020) Wnt network: a brief review of pathways and multifunctional components. Crit Rev Eukaryot Gene Expr 30(1):1–18. https://doi.org/10.1615/CritRevEukaryotGeneExpr.2019025774

    Article  PubMed  Google Scholar 

  67. Gonzalez-Reyes LE, Chiang CC, Zhang M, Johnson J, Arrillaga-Tamez M, Couturier NH, Reddy N, Starikov L et al (2019) Sonic Hedgehog is expressed by hilar mossy cells and regulates cellular survival and neurogenesis in the adult hippocampus. Sci Rep 9(1):17402. https://doi.org/10.1038/s41598-019-53192-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Troy CM, Friedman JE, Friedman WJ (2002) Mechanisms of p75-mediated death of hippocampal neurons. Role of caspases. J Biol Chem 277(37):34295–34302. https://doi.org/10.1074/jbc.M205167200

    Article  CAS  PubMed  Google Scholar 

  69. Chung L (2015) A brief introduction to the transduction of neural activity into Fos signal. Dev Reprod 19(2):61–67. https://doi.org/10.12717/DR.2015.19.2.061

    Article  PubMed  PubMed Central  Google Scholar 

  70. Angenstein F, Matthies H Jr, Staeck S, Reymann KG, Staak S (1992) The maintenance of hippocampal long-term potentiation is paralleled by a dopamine-dependent increase in glycoprotein fucosylation. Neurochem Int 21(3):403–408. https://doi.org/10.1016/0197-0186(92)90191-s

    Article  CAS  PubMed  Google Scholar 

  71. Popov N, Schmidt S, Schulzeck S, Jork R, Lossner B, Matthies H (1983) Changes in activities of fucokinase and fucosyltransferase in rat hippocampus after acquisition of a brightness discrimination reaction. Pharmacol Biochem Behav 19(1):43–47. https://doi.org/10.1016/0091-3057(83)90309-x

    Article  CAS  PubMed  Google Scholar 

  72. Gao YJ, Ji RR (2009) c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury? Open Pain J 2:11–17. https://doi.org/10.2174/1876386300902010011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sántha P, Pákáski M, Fazekas OC, Fodor EK, Kálmán S, Kálmán J Jr, Janka Z, Szabó G et al (2012) Restraint stress in rats alters gene transcription and protein translation in the hippocampus. Neurochem Res 37(5):958–964. https://doi.org/10.1007/s11064-011-0688-7

    Article  CAS  PubMed  Google Scholar 

  74. Zhang X, Chen Y, Jenkins LW, Kochanek PM, Clark RSB (2005) Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care 9(1):66–75. https://doi.org/10.1186/cc2950

    Article  CAS  PubMed  Google Scholar 

  75. He J, Yamada K, Nabeshima T (2002) A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats. Neuropsychopharmacology 26(2):259–268. https://doi.org/10.1016/SO893-133X(01)00332-3

    Article  CAS  PubMed  Google Scholar 

  76. Varela-Nallar L, Inestrosa NC (2013) Wnt signaling in the regulation of adult hippocampal neurogenesis. Front Cell Neurosci 7:100. https://doi.org/10.3389/fncel.2013.00100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cowen DS (2007) Serotonin and neuronal growth factors - a convergence of signaling pathways. J Neurochem 101(5):1161–1171. https://doi.org/10.1111/j.1471-4159.2006.04420.x

    Article  CAS  PubMed  Google Scholar 

  78. Hoffmann F, Glaeske G, Bachmann CJ (2014) Trends in antidepressant prescriptions for children and adolescents in Germany from 2005 to 2012. Pharmacoepidemiol Drug Saf 23(12):1268–1272. https://doi.org/10.1002/pds.3649

    Article  PubMed  Google Scholar 

  79. Warren BL, Mazei-Robison M, Robison AJ, Iñiguez SD (2020) Can I get a witness? Using vicarious defeat stress to study mood-related illnesses in traditionally understudied populations. Biol Psychiatry 88(5):381–391. https://doi.org/10.1016/j.biopsych.2020.02.004

    Article  PubMed  Google Scholar 

  80. Iñiguez SD, Riggs LM, Nieto SJ, Dayrit G, Zamora NN, Shawhan KL, Cruz B, Warren BL (2014) Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice. Stress 17(3):247–255. https://doi.org/10.3109/10253890.2014.910650

    Article  PubMed  PubMed Central  Google Scholar 

  81. Duque-Wilckens N, Torres LY, Yokoyama S, Minie VA, Tran AM, Petkova SP, Hao R, Ramos-Maciel S et al (2020) Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance. PNAS. https://doi.org/10.1073/pnas.2011890117

Download references

Acknowledgments

The authors thank Jorge A. Sierra-Fonseca for suggestions on earlier versions of this manuscript.

Funding

SDI acknowledges the support from the National Institute of General Medical Sciences (SC2GM109811 and SC3GM130467).

Author information

Authors and Affiliations

  1. Department of Psychology, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX, 79968, USA

    Sergio D. Iñiguez, Francisco J. Flores-Ramirez, Anapaula Themann & Omar Lira

Authors
  1. Sergio D. Iñiguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francisco J. Flores-Ramirez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anapaula Themann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Omar Lira
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SDI conceived and directed the project, analyzed data, interpreted results, and wrote the manuscript. FJF-R, AT, and OL assisted with all experiments, analyzed data, and co-wrote the manuscript. All authors reviewed and edited the manuscript.

Corresponding author

Correspondence to Sergio D. Iñiguez.

Ethics declarations

Conflict of Interest

The authors declare the they do not have conflicts of interest.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iñiguez, S.D., Flores-Ramirez, F.J., Themann, A. et al. Adolescent Fluoxetine Exposure Induces Persistent Gene Expression Changes in the Hippocampus of Adult Male C57BL/6 Mice. Mol Neurobiol 58, 1683–1694 (2021). https://doi.org/10.1007/s12035-020-02221-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-020-02221-9

Keywords

Search

Navigation

pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy