Dopamine (DA) agonists are generally more potent at presynaptic (autoreceptor) than postsynaptic DA receptor sites in the brain. For new atypical agonists (e.g. EMD 23,448, 3-PPP) the degree of selectivity is striking. The long-term objective of this project is to utilize the concepts of receptor occupancy theory as the basis for understanding such differences. The hypothesis to be tested states that a larger receptor reserve (i.e. more efficient coupling between receptor occupation and response) occurs at pre- than other, mostly postsynaptic functional DA receptors in rat striatum, which accounts for the greater potency of agonists at the former sites. The main specific aims of this project are: 1) to determine the extent of receptor reserve at various functional DA receptors in rat striatum; and 2) to determine the relative intrinsic efficacies of various classical (apomorphine, N- propylnorapomorphine) and atypical (bromocriptine, pergolide, quinpirole, ciladopa, trans-dihydrolisuride) DA agonists at functional receptors where a reserve exists. Functional dose- response curves for the various agonists will be obtained before and after partial irreversible receptor blockade with the in vivo DA receptor inactivating agent N-ethoxycarbonyl-Z-ethoxy-1,2-di- hydroquinoline (EEDQ). Using established methods, the extent of receptor reserve and the relative intrinsic efficacies of DA agonists will be determined from plots of fractional receptor occupancy vs. response. Both in vitro and in vivo models of functional activity at pre- and postsynaptic DA receptors will be assessed. In vitro, DA agonist-mediated inhibition of K+- stimulated release of 3H-DA and 14C-ACh in striatal slices, will be utilized as models of pre- and postsynaptic DA receptor function, respectively. In vitro tyrosine hydroxylation in forskolin-treated synaptosomes will also be examined in vivo, DA agonist-mediated reversal of GBL-induced accumulation of striatal L-dopa and DA agonist-induced elevation of striatal ACh levels will be utilized as models of pre- and postsynaptic DA receptor function, respectively. The results of these studies are expected to further our understanding of brain DA receptor function and provide a rational theoretical (receptor reserve) basis for new therapeutic strategies with fewer potential side effects in disease states such as schizophrenia (e.g. by utilizing selective presynaptic DA agonists to reduce dopaminergic function) and Parkinson's disease (e.g. by utilizing DA agonists with low relative intrinsic efficacies in order to selectively activate presumed supersensitive receptors).
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