Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat.
Acute administration of the psychotomimetic phencyclidine (PCP) can mimic some features of schizophrenia, while a repeated treatment regimen of PCP may provide a more effective way to model in animals the enduring cognitive dysfunction observed in many schizophrenic patients. The present study aims to investigate behavioural and neuropathological effects of sub-chronic PCP administration. The cognitive deficit induced by sub-chronic PCP was examined using a previously established operant reversal-learning paradigm. Subsequently, the effect of sub-chronic PCP on parvalbumin-immunoreactive (parvalbumin-IR) neurons was assessed using immunohistochemical techniques. Rats were trained to respond for food in an operant reversal-learning paradigm for approximately 6 weeks, followed by sub-chronic administration of PCP (2mg/kg) or vehicle twice daily for 7 days followed 7 days later by behavioural testing. Six weeks post PCP, brains were analysed using immunohistochemical techniques to determine the size and density of parvalbumin-IR in the frontal cortex and hippocampus. Sub-chronic PCP significantly reduced (p <0.001) percentage correct responding in the reversal phase relative to the initial phase, an effect that persisted throughout the experimental period (4 weeks). The density of parvalbumin-IR neurons was reduced in the hippocampus, with significant reductions in the dentate gyrus and CA2/3 regions (p <0.001). There were significant changes in the frontal cortex, with a reduction (p <0.01) in the M1 (motor area 1) region and increases in the M2 (motor area 2) region and cingulate cortex (p <0.01-p <0.001). These results parallel findings of profound hippocampal and more subtle cortical deficits of parvalbumin-IR neurons in schizophrenia, and provide evidence to suggest that sub-chronic PCP can induce a lasting cognitive deficit, an effect that may be related to the observed neuronal deficits.
Abdul-Monim
Z
Z
Bradford School of Pharmacy, University of Bradford, Bradford, UK.
Neill
J C
JC
Reynolds
G P
GP
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced*; D003216:Conditioning, Operant / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006213:Hallucinogens / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D007150:Immunohistochemistry; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D010320:Parvalbumins / Q000187:drug effects / Q000378:metabolism*; D010622:Phencyclidine / Q000008:administration & dosage / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects; D051381:Rats; D012193:Reversal Learning / Q000187:drug effects*; D012559:Schizophrenia / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
D006213:Hallucinogens; D010320:Parvalbumins; D005680:gamma-Aminobutyric Acid; D010622:Phencyclidine