Skip to main content
SpringerLink
Log in

Erythropoietin reverses the attentional set-shifting impairment in a rodent schizophrenia disease-like model

  • original investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Executive function impairment, as classically assessed using the Wisconsin Card Sort Test or intradimensional/extradimensional tests, is a key feature of schizophrenia but remains inadequately treated by existing therapies. Recently, however, erythropoietin has been shown to improve attentional set-shifting performance in schizophrenic patients.

Objective

The present study utilized the rat intradimensional/extradimensional task to investigate the potential of erythropoietin to reverse a phencyclidine-induced extradimensional shift impairment when given alone or in combination with subchronic haloperidol treatment.

Methods

Rats were subjected to a subchronic systemic administration (7 days, b.i.d) of either saline vehicle or phencyclidine (5 mg/kg) followed by a 7-day washout period during which haloperidol was given. Subsequently, rats were trained to dig in baited bowls for a food reward and to discriminate on the basis of digging media or bowl odor. In experiment 1, rats performed a series of discriminations following acute administration of vehicle, erythropoietin, or modafinil. In a second experiment, rats receiving either haloperidol in the drinking water or just normal drinking water were run in the attentional set-shifting task after acute administration of erythropoietin (1,000 or 10,000 IU/ml i.p., selected from experiment 1).

Results

The subchronic phencyclidine-induced extradimensional deficit was ameliorated by both erythropoietin and modafinil. When combined with subchronic haloperidol, the higher dose of erythropoietin tested was able to reverse the extradimensional shift impairment.

Conclusions

Overall, these findings further support the use of erythropoietin as an adjunct to antipsychotic therapy in order to address, at least part of, the cognitive dysfunction associated with schizophrenia.

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

Similar content being viewed by others

Abbreviations

CD:

Compound discrimination

ED:

Extradimensional

EDR:

Extradimensional shift reversal

EPO:

Erythropoietin

ID:

Intradimensional

ID2R:

Intradimensinal shift 2 reversal

PCP:

Phencyclidine

SD:

Simple discrimination

WCST:

Wisconsin card sorting test

References

  • Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F, Zhang M, Muller M, Hassouna I, Hannke K, Sperling S, Radyushkin K, El-Kordi A, Schulze L, Ronnenberg A, Wolf F, Brose N, Rhee JS, Zhang W, Ehrenreich H (2008) Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol 6:37

    Article  PubMed  Google Scholar 

  • Adamcio B, Sperling S, Hagemeyer N, Walkinshaw G, Ehrenreich H (2010) Hypoxia inducible factor stabilization leads to lasting improvement of hippocampal memory in healthy mice. Behav Brain Res 208:80–84

    Article  CAS  PubMed  Google Scholar 

  • Barch DM, Braver TS, Carter CS, Poldrack RA, Robbins TW (2009) CNTRICS final task selection: executive control. Schizophr Bull 35:115–135

    Article  PubMed  Google Scholar 

  • Birrell JM, Brown VJ (2000) Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20:4320–4324

    CAS  PubMed  Google Scholar 

  • Brines M, Cerami A (2005) Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 6:484–494

    Article  CAS  PubMed  Google Scholar 

  • Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97:10526–10531

    Article  CAS  PubMed  Google Scholar 

  • Byts N, Siren AL (2009) Erythropoietin: a multimodal neuroprotective agent. Exp Transl Stroke Med 1:4

    Article  PubMed  Google Scholar 

  • Ceaser AE, Goldberg TE, Egan MF, McMahon RP, Weinberger DR, Gold JM (2008) Set-shifting ability and schizophrenia: a marker of clinical illness or an intermediate phenotype? Biol Psychiatry 64:782–788

    Article  PubMed  Google Scholar 

  • Ehrenreich H, Degner D, Meller J, Brines M, Behe M, Hasselblatt M, Woldt H, Falkai P, Knerlich F, Jacob S, von Ahsen N, Maier W, Bruck W, Ruther E, Cerami A, Becker W, Siren AL (2004) Erythropoietin: a candidate compound for neuroprotection in schizophrenia. Mol Psychiatry 9:42–54

    CAS  PubMed  Google Scholar 

  • Ehrenreich H, Hinze-Selch D, Stawicki S, Aust C, Knolle-Veentjer S, Wilms S, Heinz G, Erdag S, Jahn H, Degner D, Ritzen M, Mohr A, Wagner M, Schneider U, Bohn M, Huber M, Czernik A, Pollmacher T, Maier W, Siren AL, Klosterkotter J, Falkai P, Ruther E, Aldenhoff JB, Krampe H (2007) Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 12:206–220

    Article  CAS  PubMed  Google Scholar 

  • El-Kordi A, Radyushkin K, Ehrenreich H (2009) Erythropoietin improves operant conditioning and stability of cognitive performance in mice. BMC Biol 7:37

    Article  PubMed  Google Scholar 

  • Elliott R, McKenna PJ, Robbins TW, Sahakian BJ (1995) Neuropsychological evidence for frontostriatal dysfunction in schizophrenia. Psychol Med 25:619–630

    Article  CAS  PubMed  Google Scholar 

  • Goetghebeur P, Dias R (2009) Comparison of haloperidol, risperidone, sertindole, and modafinil to reverse an attentional set-shifting impairment following subchronic PCP administration in the rat—a back translational study. Psychopharmacology (Berl) 202:287–293

    Article  CAS  Google Scholar 

  • Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am. J Psychiatry 153:321–330

    CAS  Google Scholar 

  • Harvey PD, Rabinowitz J, Eerdekens M, Davidson M (2005) Treatment of cognitive impairment in early psychosis: a comparison of risperidone and haloperidol in a large long-term trial. Am J Psychiatry 162:1888–1895

    Article  PubMed  Google Scholar 

  • Haut MW, Cahill J, Cutlip WD, Stevenson JM, Makela EH, Bloomfield SM (1996) On the nature of Wisconsin card sorting test performance in schizophrenia. Psychiatry Res 65:15–22

    Article  CAS  PubMed  Google Scholar 

  • Hengemihle JM, Abugo O, Rifkind J, Spangler E, Danon D, Ingram DK (1996) Chronic treatment with human recombinant erythropoietin increases hematocrit and improves water maze performance in mice. Physiol Behav 59:153–156

    Article  CAS  PubMed  Google Scholar 

  • Jelkmann W (2007) Erythropoietin after a century of research: younger than ever. Eur J Haematol 78:183–205

    Article  CAS  PubMed  Google Scholar 

  • Kajitani K, Thorne M, Samson M, Robertson GS (2010) Nitric oxide synthase mediates the ability of darbepoetin alfa to improve the cognitive performance of STOP null mice. Neuropsychopharmacology 35(8):1718–1728

    CAS  PubMed  Google Scholar 

  • Kumral A, Uysal N, Tugyan K, Sonmez A, Yilmaz O, Gokmen N, Kiray M, Genc S, Duman N, Koroglu TF, Ozkan H, Genc K (2004) Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats. Behav Brain Res 153:77–86

    Article  CAS  PubMed  Google Scholar 

  • Lee SM, Chou YH, Li MH, Wan FJ, Yen MH (2007) Effects of antipsychotics on cognitive performance in drug-naive schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 31:1101–1107

    Article  CAS  PubMed  Google Scholar 

  • Lu D, Mahmood A, Qu C, Goussev A, Schallert T, Chopp M (2005) Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma 22:1011–1017

    Article  PubMed  Google Scholar 

  • Madri JA (2009) Modeling the neurovascular niche: implications for recovery from CNS injury. J Physiol Pharmacol 60(Suppl 4):95–104

    PubMed  Google Scholar 

  • Mala H, Alsina CG, Madsen KS, Sibbesen EC, Stick H, Mogensen J (2005) Erythropoietin improves place learning in an 8-arm radial maze in fimbria-fornix transected rats. Neural Plast 12:329–340

    Article  CAS  PubMed  Google Scholar 

  • Mala H, Rodriguez CM, Dall JK, Mogensen J (2007) Effects of erythropoietin on posttraumatic place learning in fimbria-fornix transected rats after a 30-day postoperative pause. J Neurotrauma 24:1647–1657

    Article  PubMed  Google Scholar 

  • McClure MM, Threlkeld SW, Fitch RH (2007) Auditory processing and learning/memory following erythropoietin administration in neonatally hypoxic-ischemic injured rats. Brain Res 1132:203–209

    Article  CAS  PubMed  Google Scholar 

  • McLean SL, Beck JP, Woolley ML, Neill JC (2008) A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats. Behav Brain Res 189:152–158

    Article  CAS  PubMed  Google Scholar 

  • Miskowiak K, O’Sullivan U, Harmer CJ (2007) Erythropoietin enhances hippocampal response during memory retrieval in humans. J Neurosci 27:2788–2792

    Article  CAS  PubMed  Google Scholar 

  • Miskowiak K, Inkster B, O’Sullivan U, Selvaraj S, Goodwin GM, Harmer CJ (2008) Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration. Exp Brain Res 184:313–321

    Article  CAS  PubMed  Google Scholar 

  • Mogensen J, Miskowiak K, Sorensen TA, Lind CT, Olsen NV, Springborg JB, Mala H (2004) Erythropoietin improves place learning in fimbria-fornix-transected rats and modifies the search pattern of normal rats. Pharmacol Biochem Behav 77:381–390

    Article  CAS  PubMed  Google Scholar 

  • Mogensen J, Boyd MH, Nielsen MD, Kristensen RS, Mala H (2008a) Erythropoietin improves spatial delayed alternation in a T-maze in rats subjected to ablation of the prefrontal cortex. Brain Res Bull 77:1–7

    Article  CAS  PubMed  Google Scholar 

  • Mogensen J, Jensen C, Kingod SC, Hansen A, Larsen JA, Mala H (2008b) Erythropoietin improves spatial delayed alternation in a T-maze in fimbria-fornix transected rats. Behav Brain Res 186:215–221

    Article  CAS  PubMed  Google Scholar 

  • Olsen CK, Brennum LT, Kreilgaard M (2008) Using pharmacokinetic-pharmacodynamic modelling as a tool for prediction of therapeutic effective plasma levels of antipsychotics. Eur J Pharmacol 584:318–327

    Article  CAS  PubMed  Google Scholar 

  • Pantelis C, Barber FZ, Barnes TR, Nelson HE, Owen AM, Robbins TW (1999) Comparison of set-shifting ability in patients with chronic schizophrenia and frontal lobe damage. Schizophr Res 37:251–270

    Article  CAS  PubMed  Google Scholar 

  • Pillai A, Dhandapani KM, Pillai BA, Terry AV Jr, Mahadik SP (2008) Erythropoietin prevents haloperidol treatment-induced neuronal apoptosis through regulation of BDNF. Neuropsychopharmacology 33:1942–1951

    Article  CAS  PubMed  Google Scholar 

  • Robertson GS, Kajitani K, Samson M (2010) Nitric oxide synthase mediates the ability of darbepoetin alfa to attenuate pre-existing spatial working memory deficits in rats subjected to transient global ischemia. J Pharmacol Exp Ther 333(2):437–444

    Article  PubMed  Google Scholar 

  • Rodefer JS, Murphy ER, Baxter MG (2005) PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats. Eur J Neurosci 21:1070–1076

    Article  PubMed  Google Scholar 

  • Statler PA, McPherson RJ, Bauer LA, Kellert BA, Juul SE (2007) Pharmacokinetics of high-dose recombinant erythropoietin in plasma and brain of neonatal rats. Pediatr Res 61:671–675

    CAS  PubMed  Google Scholar 

  • Tonges L, Schlachetzki JC, Weishaupt JH, Bahr M (2007) Hematopoietic cytokines—on the verge of conquering neurology. Curr Mol Med 7:157–170

    Article  PubMed  Google Scholar 

  • Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ (2004) Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology 29:1363–1373

    Article  CAS  PubMed  Google Scholar 

  • Waters KA, Burnham KE, O’connor D, Dawson GR, Dias R (2005) Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat. J Psychopharmacol 19:149–158

    Article  CAS  PubMed  Google Scholar 

  • Xiong Y, Mahmood A, Meng Y, Zhang Y, Qu C, Schallert T, Chopp M (2009) Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose. J Neurosurg (in press)

  • Yatsiv I, Grigoriadis N, Simeonidou C, Stahel PF, Schmidt OI, Alexandrovitch AG, Tsenter J, Shohami E (2005) Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J 19:1701–1703

    CAS  PubMed  Google Scholar 

  • Yoo JY, Won YJ, Lee JH, Kim JU, Sung IY, Hwang SJ, Kim MJ, Hong HN (2009) Neuroprotective effects of erythropoietin posttreatment against kainate-induced excitotoxicity in mixed spinal cultures. J Neurosci Res 87:150–163

    Article  CAS  PubMed  Google Scholar 

  • Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The authors would like to acknowledge Dr L. Torup for advice on erythropoietin use and Dr N. Plath for critical review of the manuscript.

Author information

Author notes

  1. Pascal Jean Denis Goetghebeur & Rebecca Dias

    Present address: Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK

Authors and Affiliations

  1. H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Pascal Jean Denis Goetghebeur, Linda Lerdrup, Anders Sylvest & Rebecca Dias

Authors
  1. Pascal Jean Denis Goetghebeur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linda Lerdrup
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anders Sylvest
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rebecca Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pascal Jean Denis Goetghebeur.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goetghebeur, P., Lerdrup, L., Sylvest, A. et al. Erythropoietin reverses the attentional set-shifting impairment in a rodent schizophrenia disease-like model. Psychopharmacology 212, 635–642 (2010). https://doi.org/10.1007/s00213-010-1990-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-010-1990-9

Keywords

Search

Navigation