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.

Abstract

RATIONALE:

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.

CONCLUSION:

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.

• Authors: Brian Villumsen Broberg, Birte Yding Glenthøj, Rebecca Dias, Dorrit Bjerg Larsen, Christina Kurre Olsen
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 206 Issue 4 Pg. 631-40 (Nov 2009) ISSN: 1432-2072 [Electronic] Germany
• PMID: 19390843 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• 1-(quinoxalin-6-ylcarbonyl)piperidine
• Antipsychotic Agents
• Dioxoles
• Imidazoles
• Indoles
• Piperidines
• sertindole
• Phencyclidine

Topics

• Animals
• Antipsychotic Agents (administration & dosage, pharmacology)
• Attention (drug effects)
• Dioxoles (administration & dosage, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Male
• Phencyclidine (administration & dosage, toxicity)
• Piperidines (administration & dosage, pharmacology)
• Rats
• Schizophrenia (drug therapy, physiopathology)