In this project PCP or ketamine are used to model some aspect of schizophrenia in the rhesus monkey and healthy individuals with the underlying assumption that pharmacological approaches that reduce the behavioral disruptions produced by these psychotomimetic drugs may have therapeutic potential for treatment of schizophrenia. Complementary clinical and pre-clinical studies are designed to test the novel hypothesis, supported by preliminary data, that while PCP and ketamine block the NMDA subtype of glutamate receptors, they produce glutamatergic hyperactivity at non-NMDA receptors. Reductions of glutamatergic neurotransmission therefore would work to ameliorate some of the symptomatology associated with these drugs. The basic studies will utilize microdialysis in chaired monkeys engaged in working memory and other related tasks. The clinical studies will utilize fMRI measures in healthy individuals as well as treatment studies in schizophrenics. Parallel pharmacological strategies including glutamate release blockers and drugs that target glutamate metabotropic receptors will be used to reduce glutamateric neurotransmission in preclinical and clinical studies. This research will result in a better understanding of the functional neuroanatomy and neurochemistry associated with PCP- and ketamine-induced behavioral disruptions and may result in novel treatments for the deficit symptoms of schizophrenia for which the current modes of treatment are generally ineffective.
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