Development of Receptor and Metabolic Models of Iodothyronine Processing in Adult Male Rats We have proposed that altered rates and routes of thyroid hormone processing in the CNS are important determinants of behavioral and mood disorders. The studies described in this application will lay the groundwork for testing this hypothesis in patients with affective illness. Serial film autoradiography and iodocompound analyses will be performed on brains obtained from euthyroid male rats given a single i.v. injection of 125I-triiodothyronine (T3) or 125I-thyroxine (T4). Concentrations of labeled and endogenous iodocompounds in the same brains will be determined utilizing intervening tissue sections not used in the autoradiographic process. These intervening sections will be assembled into pools representative of brain regions of interest, extracted, and the extracts analyzed by HPLC and RIA. Radiochemical analyses of sequential blood samples drawn during the in vivo survival of the animals will be used for describing peripheral T3 and T4 kinetics. This information, combined with the brain biochemical data arid the results of computer-assisted densitometric analysis of the autoradiograms, will provide values for the necessary and sufficient number of parameters required for constructing models of iodothyronine processing in the adult male rat brain. Because recent findings demonstrate that thyroid hormone processing in rat brain differs from region to region, we will construct models of T3 specific binding and T3 and T4 metabolism in brain which will yield regional rate constants for uptake, binding and turnover. As required for our long-term goals, the availability of models of regional thyroid hormone kinetics will enable us to determine whether gender, age, thyroid status, environmental stress or psychotropic drug administration influence brain iodothyronine processing in the rat. They are also required to determine the potential (and conditions) for brain imaging of human subjects given i.v. 123I-iodothyronines.
