We propose to examine the binding and functional properties of Alpha-adrenergic receptor subtypes in rat brain, their localization to specific cell types and nerve tracts, the regulation of receptor density and responsiveness by changes in afferent input, and the interaction of various psychoactive drugs with these receptors in the brain. Alpha1- and Alpha2-adrenergic receptors will be directly labelled using the antagonist radioligands 125I-BE2254 and 3H-rauwolscine. Measurement of functional responses to receptor stimulation will include norepinephrine-induced increases in 3H-inositol metabolism and clonidine-induced decreases in cyclic AMP levels in brain slices by Alpha1- and Alpha2-adrenergic receptors respectively. Decreases in 3H-5-hydroxytryptamine release by Alpha2-adrenergic receptor stimulation will also be examined in rat cerebral cortex. Correlation between the potencies of antagonists in competing for radioligand binding sites and inhibiting receptor-mediated responses will provide evidence that the radioligands are labelling the appropriate receptor sites. Comparison of the potencies of agonists in binding to the receptors and activating functional responses will estimate the relationship between receptor occupancy and tissue response. The existence of spare receptors will be examined by decreasing receptor density with phenoxybenzamine and examining responsiveness under conditions of decreased receptor density. Localization of receptor subtypes to specific cell populations and nerve tracts will be accomplished by examination of receptor density after chemical lesions and in bulk isolated cell populations. The regulation of receptor density and responsiveness by alterations in the noradrenergic input, and chronic agonist or antagonist treatment, will provide evidence on mechanisms controlling the adaptive responsiveness of these receptors. Effects observed after chronic treatment with psychoactive drugs will provide evidence as to which drugs have significant interactions with these receptors. These experiments will increase our knowledge of the properties, localization and regulation of Alpha-adrenergic receptor subtypes in rat brain. This will be useful in understanding the actions of norepinephrine in the brain, as well as in evaluating the central nervous system effects of a number of drugs that interact with Alpha-adrenergic receptors and that are in current medical usage.
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