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.
BACKGROUND
Selective cognitive impairments, including those of executive function as assessed using the Wisconsin Card Sort Test or intradimensional-extradimensional (ID-ED) tests, are a key feature of schizophrenia but remain inadequately treated by existing therapies. Recently, however, modafinil has been shown to improve attentional set-shifting performance in patients with schizophrenia.


OBJECTIVE
The present study evaluated the recently described analogous rat ID-ED attentional set-shifting task by investigating the effects of various pharmacological challenges to a phencyclidine (PCP)-induced ED shift impairment, namely, haloperidol, risperidone, sertindole, and modafinil.


METHODS
Rats were subjected to a subchronic systemic administration of either saline vehicle or PCP (5 mg/kg i.p. b.i.d. for 7 days) followed by a 7-day washout period. During this period, rats were trained to dig in baited bowls for a food reward and to discriminate based on odor or digging media. In a single test session conducted the day after the washout period (day 8), rats performed a series of discriminations following acute administration of either vehicle, or haloperidol (0.1 mg/kg s.c.), or risperidone (0.2 mg/kg i.p.), or sertindole (1.25 mg/kg p.o.) or modafinil (64 mg/kg p.o.).


RESULTS
The subchronic PCP-induced ED deficit was ameliorated by sertindole and modafinil but not by haloperidol or risperidone.


CONCLUSIONS
Overall, these findings further support that the rat ID-ED test in subchronic PCP-treated rats has utility and validity as a preclinical model of the cognitive symptoms of schizophrenia and demonstrates back-translational potential.
Goetghebeur
Pascal
P
H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. RDI@lundbeck.com
Dias
Rebecca
R
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001288:Attention / Q000187:drug effects*; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists; D006220:Haloperidol / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D000077408:Modafinil; D010622:Phencyclidine; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D018967:Risperidone / Q000494:pharmacology*; D012565:Schizophrenic Psychology
D014150:Antipsychotic Agents; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D007211:Indoles; C066304:sertindole; D010622:Phencyclidine; D006220:Haloperidol; D018967:Risperidone; D000077408:Modafinil