This is a proposal to bring molecular techniques into a well-established behavioral/pharmacology laboratory at the University of Hawaii, in order to facilitate a research program on the relationship between CRF systems and anxiety-related behaviors and contribute to the development of Neurosciences research and training at this minority institution. This will involve the use of CRF receptor knock out mice, and, ex vivo analysis of regional brain receptor subtype occupancy associated with acidic astressin, in the context of two ethological procedures, the Mouse Defense Test Battery (MDTB), and the Rat Exposure Test (RET). These tests measure defensive behaviors that have been previously validated as selectively responsive to anxiolytic and panicolytic drugs. Based on preliminary findings, the potent CRF antagonist acidic astressin reduces specific defensive behaviors of these tests. The research program will extend these results and determine their mechanisms of action through use of agonists and antagonists at different CRF receptor subtypes. It will also evaluate the defensive behaviors of CRF receptor subtype knockout mice, developed by the Spiess laboratory, to verify these mechanisms. Ex vivo ligand binding and quantitative autoradiography will be used to determine CRF receptor occupancy following administration of acidic astressin at different dose levels, permitting evaluation of the relationship of receptor occupancy at these levels to their effects on particular defensive behaviors. These studies will thus utilize a range of new genetic and molecular techniques in analysis of the role of CRF systems in anxiety, enhancing understanding of these mechanisms and advancing the Neuroscience research capabilities of the University.
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