The overall objective of this application is the investigation of dopamine (DA) and prostaglandins utilizing physiological, biochemical, histological, and behavioral techniques. Four projects are included. Project I: Investigation of Receptors in Physiological Models. The major portion of this project is to study the chemical requirements of two DA receptors, DA1 and DA2. DA1 receptors subserve smooth muscle relaxation (vasodilation). DA2 receptors subserve inhibition of sympathetic nerves and prolactin release. DA1 agonists will be administered to anesthetized dogs to determine effects on cardiac contractile force, arterial blood pressure, cardiac output, and regional blood flow. Studies also will be conducted in isolated canine and rabbit blood vessels. DA1 and DA2 antagonists will also be investigated. Prostanoid receptors and new prostaglandin agonists and antagonists will be studied by the same techniques. Project II: The Physiological Role of DA and Other Endogenous Substances in the Neuronal Control of Renal Function. The origin of previously identified DA containing nerves will be sought by use of anatomical and histochemical techniques and their potential role will be investigated by studying the effect of selective lesions, nerve stimulation and use of specific DA antagonists. Project III: Biochemical Investigations of DA and Other Neurotransmitters. Structure activity relationships and potency series of DA1 and DA2 agonists and antagonists obtained in physiological models will be compared with data obtained in two biochemical receptor models: stimulation of adenylate cyclase and ligand binding assays. Potential mechanisms of the antihypertensive actions of DA agonists will be studied by intracerebroventricular injections and injections into the nucleus tractus solitarius of spontaneously hypertensive rats. Effects on blood pressure and neurotransmitter content in the nucleus tractus solitarius also will be obtained. The third protocol is designed so that chemical and biochemical assays can be obtained during long-term clinical studies of DA agonists in order to determine whether correlations will exists between hemodynamic and clinical changes and these assays. Project IV: Behavioral Analysis of Central Nervous System DA Receptors. This project will provide behavioral data relevant to the existence of multiple DA receptors in the central nervous system by drug discrimination procedures in rats. The participants and facilities in each project will be available for investigations in other projects to facilitate and enhance the research efforts.
