Chronic infusion of PCP via osmotic mini-pumps: a new rodent model of cognitive deficit in schizophrenia characterized by impaired attentional set-shifting (ID/ED) performance

J Neurosci Methods. 2009 Dec 15;185(1):66-9. doi: 10.1016/j.jneumeth.2009.09.014. Epub 2009 Sep 15.

Abstract

The identification of animal disease-like models for cognitive symptoms in schizophrenia is of central importance to the successful development of pharmacological therapies for psychosis resulting in a functional outcome in patients. Executive function is one of the most severely affected cognitive domains in schizophrenia that remains inadequately treated by existing therapies. The rat attentional set-shifting (or intra-dimensional-extra-dimensional (ID/ED)) task has been developed to test executive function in rodents and successful translation of pre-clinical data into the clinical setting now depends on the identification of a predictive animal disease-like model. The present study investigates whether a continuous 14-day mini-pump infusion of the non-competitive NMDA receptor antagonist phencyclidine (PCP) leads to a deficit in the ID/ED task, and subsequently evaluates the effect of modafinil in this model. Lister hooded rats were implanted subcutaneously with osmotic mini-pumps containing saline or PCP (15 mg/kg/day) for 14 days followed by a 7-day drug-free recovery phase. Rats were then tested in the ID/ED task following an acute injection of either vehicle or modafinil. PCP-treated animals displayed a selective deficit at the ED shift stage resembling that observed in schizophrenic patients. This deficit was reversed by an acute injection of modafinil. The PCP-induced impairment and its reinstatement by modafinil are quantitatively and qualitatively similar to that described earlier by our group following sub-chronic intraperitoneal PCP administration, indicative that sub-chronic PCP infusion via osmotic mini-pumps may represent an attractive alternative to the systemic administration protocols generally employed to date.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Attention / drug effects
  • Attention / physiology
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Behavioral Sciences / instrumentation
  • Behavioral Sciences / methods
  • Benzhydryl Compounds / pharmacology
  • Brain / drug effects
  • Brain / physiopathology
  • Central Nervous System Stimulants / pharmacology
  • Cognition Disorders / chemically induced*
  • Cognition Disorders / physiopathology
  • Disease Models, Animal
  • Drug Administration Schedule
  • Hallucinogens / administration & dosage
  • Hallucinogens / toxicity
  • Infusion Pumps, Implantable / trends*
  • Male
  • Modafinil
  • Neuropharmacology / instrumentation*
  • Neuropharmacology / methods
  • Neuropsychological Tests
  • Neurosciences / instrumentation
  • Neurosciences / methods
  • Phencyclidine / administration & dosage*
  • Phencyclidine / toxicity
  • Rats
  • Schizophrenia / chemically induced*
  • Schizophrenia / physiopathology
  • Schizophrenic Psychology

Substances

  • Antipsychotic Agents
  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Hallucinogens
  • Phencyclidine
  • Modafinil