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.
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.
Pedersen
Christian Spang
CS
Department of Neurobiology, H. Lundbeck A/S, Valby, Denmark. CHSP@lundbeck.com
Goetghebeur
Pascal
P
Dias
Rebecca
R
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001288:Attention / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001525:Behavioral Sciences / Q000295:instrumentation / Q000379:methods; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006213:Hallucinogens / Q000008:administration & dosage / Q000633:toxicity; D015918:Infusion Pumps, Implantable / Q000639:trends*; D008297:Male; D000077408:Modafinil; D009480:Neuropharmacology / Q000295:instrumentation* / Q000379:methods; D009483:Neuropsychological Tests; D009488:Neurosciences / Q000295:instrumentation / Q000379:methods; D010622:Phencyclidine / Q000008:administration & dosage* / Q000633:toxicity; D051381:Rats; D012559:Schizophrenia / Q000139:chemically induced* / Q000503:physiopathology; D012565:Schizophrenic Psychology
D014150:Antipsychotic Agents; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D006213:Hallucinogens; D010622:Phencyclidine; D000077408:Modafinil