Neurochemical substrates of cognitive dysfunction produced by the psychotomimetic drug phencyclidine.

摘要

Administration of non-competitive NMDA/glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, to humans induces a broad range of schizophrenic-like symptomatology, findings that have contributed to a hypoglutamatergic hypothesis of schizophrenia. Moreover, a history of experimental investigations of the effects of these drugs in animals suggests that NMDA receptor antagonists may model some behavioral symptoms of schizophrenia in non-human subjects. This thesis has attempted to directly address the nature and neurochemical substrates of cognitive dysfunction produced by subchronic exposure to the PCP by utilizing both rodent and non-human primate subjects. The results suggest that subchronic exposure to PCP can produce a spectrum of behavioral deficits that have face and construct validity for several cognitive sequelae of schizophrenia. In addition, the data demonstrate that dopaminergic dysfunction within the prefrontal cortex and striatum are strongly associated with the behavioral deficits, suggesting that alterations in forebrain dopamine transmission may produce the drug-induced behavioral deficits. Finally, pharmacological evidence indicates that the cognitive impairments produced by subchronic exposure to PCP may have validity for predicting the superior therapeutic efficacy of novel antipsychotic drugs. These data are synthesized to argue that cortical dysfunction produced by subchronic exposure to PCP may be a useful model for investigating the pathophysiology and pharmacology of psychiatric disorders associated with cortical dopamine dysfunction.