BIOCHEMISTRY OF NEUROTRANSMITTER RECEPTORS

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In this application we propose to investigate the genetic control on dopamine receptors and the way in which genetic variations influence behavioral responses to psychopharmacologic agents. Dopamine receptors are measured in the olfactory tubercle and corpus striatum using 3H-ADTN, a dopaminergic agonist, and 3H-spiroperidol, a dopamine receptor antagonist, as radioligands. Among eleven inbred mouse strains, variations in the number of dopamine receptors up to two-fold are observed. In contrast, no differences in radioligand affinity are seen. ADTN labels different sites than those labelled by spiroperidol. Spiroperidol binds to both serotonin and dopamine sites in the olfactory tubercle, but binds primarily to dopaminergic sites in the striatum. The number of ADTN or spiroperidol binding sites in the striatum does not correlate with the number of radioligand binding sites in the olfactory tubercle, suggesting that genetic controls on dopamine receptors operate independently in the olfactory tubercle and striatum. If this is true, the finding is of considerable potential clinical importance. The studies proposed in this application seek to further characterize ADTN and spiroperidol binding sites in both the olfactory tubercle and striatum. This is to differentiate serotonin from mouse strains to determine the number of genes involved in transmission of each ligand binding sites, the existence of structural gene variants, whether dopamine receptors in one region are under independent genetic control from receptors in the other region, and the mechanisms of gene control over dopamine receptors. The genetic data will then be used in psychopharmacology studies with amphetamine and haloperidol. These studies will determine if genetic differences in behaviors induced by administration of these dopaminergically-active drugs are associated with inheritance of dopamine receptors.