title: Effects of quetiapine and sertindole on subchronic ketamine-induced deficits in attentional set-shifting in rats.
abstract: BACKGROUND
  Prefrontal cortical dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. Nevertheless, the effectiveness of second-generation antipsychotic drugs in treating specific prefrontal dysfunctions remains equivocal.
  
  
  OBJECTIVE
  To model schizophrenia-like cognitive inflexibility in rats, we evaluated the effects of repeated administration of ketamine, the noncompetitive antagonist of the N-methyl-D: -aspartate receptor, after a washout period of 14 days in the attentional set-shifting task (ASST). Next, we investigated whether the atypical antipsychotics quetiapine and sertindole would alleviate the ketamine-induced set-shifting impairment.
  
  
  METHODS
  Ketamine (30 mg/kg) was administered intraperitoneally to rats once daily for 5 or 10 consecutive days to assess its efficacy in producing cognitive impairment. The ASST was performed 14 days following the final drug administration. Quetiapine (0.63, 1.25 or 2.5 mg/kg) or sertindole (2.5 mg/kg) was administered per os 120 min before testing.
  
  
  RESULTS
  The results of the present study demonstrate that ketamine treatment for 10 but not 5 days significantly and specifically impaired rats' performance in the extra-dimensional shift (EDs) stage of the ASST. This cognitive inflexibility was reversed by acute administration of sertindole or quetiapine. Quetiapine also promoted set-shifting in cognitively unimpaired control animals.
  
  
  CONCLUSIONS
  The data presented here show that subchronic administration of ketamine induces cognitive inflexibility after a washout period. This cognitive deficit likely reflects clinically relevant aspects of cognitive dysfunction encountered in schizophrenic patients. The beneficial effects of quetiapine on set-shifting may have therapeutic implications for the treatment of schizophrenia and other disorders associated with frontal-dependent cognitive impairments.
authors.affiliation: Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland. nikifor@if-pan.krakow.pl
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Nikiforuk
authors.forename: Piotr
authors.initials: P
authors.lastname: Popik
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001288:Attention / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000503:physiopathology; D003987:Dibenzothiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007649:Ketamine / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D000069348:Quetiapine Fumarate; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D007211:Indoles; D000069348:Quetiapine Fumarate; D007649:Ketamine; C066304:sertindole