This is a request for an ADAMHA RSDA (Level I) award. The focus of this project is the study of the distribution and function of elements of the (kappa) opioid system in selected neocortical regions of the mammalian brain, culminating with the study of this system in schizophrenia. The hypothesis being tested in this series of studies is that the tone of the kappa opioid systems may be altered in the neocortex in schizophrenia. The kappa opioid receptor is of potential interest to the study of this illness: administration of kappa-agonists to normal humans produces psychotic symptoms, and treatment with opioid receptor antagonists can diminish psychotic symptoms in schizophrenic patients. Kappa receptors, as well as cell bodies containing prodynorphin-related peptides, the family of endogenous kappa ligands, are found in regions of the brain that would be suspected of being involved in the pathogenesis and production of symptoms in schizophrenia, especially the neocortex. Further, the kappa opioid system may enjoy reciprocal regulation with the major dopaminergic projections felt to be disrupted in schizophrenia. The focus of this proposal, then, is to systematically examine this opioid system and its interactions with the mesocortical and mesolimbic dopaminergic projections in discrete areas of the neocortex, at multiple regulatory levels. This will be accomplished by determining amounts of prodynorphin mRNA and peptide forms, as well as opiate receptor affinity and density, in selected neocortical and associated areas. Subsequently, levels of elements of the mesocortical and mesolimbic dopamine projections will be superimposed onto this information. The co-regulation of these two systems will next be studied, by examining neocortical components of the kappa and dopaminergic systems following pharmacological manipulation with kappa-ergic and dopaminergic agents. Finally, these systems will be studied in neocortical areas of postmortem brains from schizophrenic subjects, as well as in cerebrospinal fluid of schizophrenic patients. These studies will involve a convergence of techniques, including pharmacological manipulations, mRNA quantitation, peptide radioimmunoassay and gel filtration chromatography, receptor binding assays, receptor autoradiography, in situ hybridization, and semi-quantitative image analysis. A training program is also outlined, involving staged learning experiences designed to parallel the flow and the logic of the proposed studies. This project will take place within the Mental Health Research Institute and the Department of Psychiatry at the University of Michigan, and also includes several carefully selected, focused external learning experiences. The end result of this five year project will be the production of an investigator capable of performing original studies at the interface between psychiatry and the neurosciences.
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