The behavioral syndrome produced by the noncompetitive NMDA receptor antagonist PCP, and its analogue ketamine, bears a strong resemblance to core symptoms of schizophrenia. In this application, PCP and ketamine are used to model some aspects of schizophrenia in the laboratory animal with the underlying assumption that gaining insight to the mechanism of action of PCP will facilitate the development of pharmacological approaches that reverse PCP-induced disruption of normal behavior, and that may have therapeutic benefits for schizophrenia. Based on observations during the last granting period, including the finding that PCP and ketamine increase GLU release in the prefrontal cortex, it is hypothesized that PCP and ketamine increase the synaptic availability of GLU in the prefrontal cortex and thereby activate non-NMDA GLU receptors. Hyperstimulation of non-NMDA GLU receptors, i.e., AMPA, kainate, or metabotropic receptors, in turn produces a limbic hyperDAergic state and other secondary events that disrupt normal behavior. The proposed research aims at elucidating mechanism(s) by which ketamine and PCP increase GLUrgic neurotransmission and establishing that reduction of GLUrgic neurotransmission at non-NMDA receptors will ameliorate the disruption of normal behavior by PCP and ketamine. The proposed studies will be performed primarily in the rat. In addition, a few key microdialysis experiments will be performed in the awake rhesus monkey to establish that our rodent findings can be extended to the primate.
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