Erythropoietin reverses the attentional set-shifting impairment in a rodent schizophrenia disease-like model.
BACKGROUND
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.
Goetghebeur
Pascal Jean Denis
PJ
H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark. pascal.goetghebeur@pfizer.com
Lerdrup
Linda
L
Sylvest
Anders
A
Dias
Rebecca
R
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001288:Attention / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001559:Benzhydryl Compounds / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000494:pharmacology*; D056344:Executive Function / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D000077408:Modafinil; D009483:Neuropsychological Tests; D010622:Phencyclidine; D051381:Rats; D011994:Recombinant Proteins; D012201:Reward; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy*; D012565:Schizophrenic Psychology
D014150:Antipsychotic Agents; D001559:Benzhydryl Compounds; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; D010622:Phencyclidine; D006220:Haloperidol; D000077408:Modafinil