Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia--sub-chronic and early postnatal PCP treatment in attentional set-shifting.
BACKGROUND
Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present.


OBJECTIVE
The current study evaluated the effect of ampakine CX516 in reversing deficits in executive functioning as represented in two animal models of schizophrenia and assessed by a rodent analog of the intradimensional-extradimensional (ID-ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models.


METHODS
Animals were subjected to (a) sub-chronic or (b) early postnatal phencyclidine (PCP) treatment regimes: (a) Administration of either saline or PCP (5 mg/kg, intraperitonally b.i.d. for 7 days) followed by a 7-day washout period and testing on day 8. (b) On postnatal days (PNDs) 7, 9, and 11, rats were subjected to administration of either saline or PCP (20 mg/kg, subcutaneously (s.c.)) and tested on PNDs 56-95, after reaching adulthood. The single test session required rats to dig for food rewards in a series of discriminations following acute administration of either vehicle, or CX516 (5-40 mg/kg, s.c.), or sertindole (1.25 mg/kg, perorally).


RESULTS
The specific extradimensional deficits produced by sub-chronic or early postnatal PCP treatment were significantly attenuated by sertindole and dose-dependently by CX516.


CONCLUSIONS
Findings here further establish PCP treatment as model of executive functioning deficits related to schizophrenia and provide evidence that direct glutamatergic interventions could improve these, when assessed in the ID-ED attentional set-shifting task.
Broberg
Brian Villumsen
BV
Department of In Vivo Neurobiology, H. Lundbeck A/S, Ottiliavej 9, Valby, Denmark. bbs@lundbeck.com
Glenthøj
Birte Yding
BY
Dias
Rebecca
R
Larsen
Dorrit Bjerg
DB
Olsen
Christina Kurre
CK
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001288:Attention / Q000187:drug effects; D004149:Dioxoles / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010622:Phencyclidine / Q000008:administration & dosage / Q000633:toxicity*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology
C097396:1-(quinoxalin-6-ylcarbonyl)piperidine; D014150:Antipsychotic Agents; D004149:Dioxoles; D007093:Imidazoles; D007211:Indoles; D010880:Piperidines; C066304:sertindole; D010622:Phencyclidine