The overall goal in the studies described in this proposal is to increase our understanding of the function and regulation of dopamine receptors. We are attempting to develop a means of quantitatively measuring dopamine receptor subtypes in complex hetereogeneous tissues such as regions of the mammalian central nervous system. The approach described in this proposal is to study the pharmacological specificity of so-called D-1 and D-2 receptors in tissues which contain only one of these two receptor subtypes. Based on our knowledge of the properties of these subtypes the distribution in regions of the mammalian central nervous system will be determined. Effects of surgical and pharmacological manipulations on the densities and properties of central D-1 and D-2 receptors will be investigated. The manipulations chosen will be those that will cause specific losses of given populations of neurons and/or will cause changes in the degree of occupancy of dopamine receptor subtypes. The amount of 3H-ADTN binding is increased in the presence of either ATP or GTP. The possibility that ADTN is inducing phosphorylation of specific membrane proteins will be investigated. Finally, in vitro studies of the regulation of dopamine receptor subtypes will be carried out. The effects of purine nucleotides and of mono and divalent cations on dopamine receptor subtypes will be investigated. Effects of varying membrane fluidity on dopamine receptors and on dopamine receptor stimulated adenylate cyclase activity will also be assessed. It is hoped that the in vivo and in vitro experiments will result in an increase in our understanding of the mechanism of action of various pharmacologic agents which are thought to act through stimulation or inhibition of dopamine receptors. The experiments should thus provide insights that will be useful in terms of the development of new, hopefully more selective, therapeutic agents.
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