Perinatal Neurodegeneration and Schizophrenia

University Of Texas Medical Br Galveston, Galveston TX

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Abstract

DESCRIPTION (provided by applicant): Recent studies on the behavioral and neurotoxic effects of NMDA receptor antagonists such as MK-801 and phencyclidine (PCP) have led to the suggestion that glutamatergic hypofunction may be part of the etiology of schizophrenia. Imaging and postmortem studies have pointed to diminished cortical function in schizophrenia, possibly resulting from altered development stemming from an undefined late prenatal insult. This laboratory has found that perinatal PCP administration (PN7, 9, 11) results in evidence of selective cortical apoptosis (PN 12) associated with behavioral changes including diminished baseline prepulse inhibition of acoustic startle (PN 24-28) and a sensitized locomotor response to PCP challenge (PN 42). Each of these effects was prevented by olanzapine pretreatment. Thus, it is proposed that PCP-induced neurotoxicity plays a significant role in the mechanism inderlying the behavioral alterations. This application is to test this, and other related hypotheses. First, the time course and dose- response for PCP-induced neurotoxicity and behavioral effects will be compared in an effort to separate these phenomena. Then, several selective receptor antagonists will be tested in an effort to again separate the behavioral and neurotoxic effects and to provide information concerning the neurotransmitter receptors involved. Specific antagonists of nitric oxide synthase and superoxide anion will also be tested to try to link the neurotoxic mechanism with the behaviors. The role of NMDA receptor upregulation and function in these processes will be tested using a pharmacological approach. Premature loss of striatal PSA-NCAM at PN 15 suggested the possibility that PCP treatment results in altered striatal function. Measurement of striatal glutamatergic innervation and transmitter release regulation will test this hypothesis. Finally, preliminary data suggesting that superoxide anion, SF-KB nuclear translocation and altered expression of Bax and Bcl-XL are involved in PCP-induced apoptosis will be further pursued and ultimately tested pharmacologically to determine their role in the in vivo effects of PCP. These data will increase the understanding of the mechanisms of PCP-induced neuro- and behavioral toxicity in the newborn rat and could provide a model of schizophrenia with both construct and face validity. These data will also provide information about the possible consequences of abuse of NMDA antagonists including PCP and ethanol late in pregnancy.