Recently, and in the past several years, techniques have been developed for the direct measurement of receptor molecules in brain. Many psychotropic drugs exert their action directly or indirectly through these receptors and postmortem studies of human tissues have revealed that these receptors are altered in a variety of neuropsychiatric diseases. Thus, it seems possible that receptor alterations may be the causes of at least some of these diseases. This proposal deals with studying receptors in animal and human brain. A receptor of main interest is the D2-dopamine receptor. Antipsychotic drugs are thought to exert their action, at least in part, by blocking D2-dopamine receptors. The question as to whether or not increases in dopamine receptor levels are at least partly the cause of schizophrenia or are due to drug treatmet has been debated heavily. A goal of this proposal is to localize, map, annd measure dopamine receptors in primate brain. This will be carried out by routine receptor autoradiographic techniques which utilize tissue obtained at autopsy as well as by PET scanning techniques which are noninvasive and allow a measurement of receptors in vivo. The evolution of PET scanning techniques for measuring receptors is a significant advance because, for the first time, it will be possible to measure dopamine receptors and other receptors in clinical populations at various stages of their disease. Another goal of this proposal is to map CRF receptors which are an important component of the hypothalamic-pituitary-adrenal system which is a key physiological system in stress. In general, receptor maps point out sites of drug action in brain and will help explain how various drugs exert their effects. Another goal of this proposal is to explore the possibility of making several technical improvements in our light microscopic autoradiographic techniques. These techniques are being used by ever increasing numbers of people and several difficult technical problems remain. A major question in the field of receptor mapping is which specific cells have the receptors. We will attempt to develop light microscopic methods for identifying specific neurons which produce specific receptor types. Considering all of our goals together, preliminary experiments indicate that significant advances can be made with every goal.
