Central actions of a novel and selective dopamine antagonist
Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D/sub 1/ class, which is linked to the stimulation of adenylate cyclase-activity, and the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D/sub 1/ class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of (/sup 3/H)-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D/sub 1/ receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for (/sup 3/H)-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D/sub 1/ receptors and (/sup 3/H)-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D/sub 1/ dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated.
- Research Organization:
- North Carolina Univ., Chapel Hill (USA)
- OSTI ID:
- 6941177
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
AMINES
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZINES
BODY
BRAIN
CARDIOTONICS
CARDIOVASCULAR AGENTS
CENTRAL NERVOUS SYSTEM
CYCLASES
DISTRIBUTION
DOPAMINE
DRUGS
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
INHIBITION
LABELLED COMPOUNDS
LYASES
MEMBRANE PROTEINS
NERVOUS SYSTEM
NEUROREGULATORS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PHENOLS
PHYSIOLOGY
POLYPHENOLS
PROTEINS
RECEPTORS
SUBCELLULAR DISTRIBUTION
SYMPATHOMIMETICS
TRITIUM COMPOUNDS