Molecular Pharmacology, Vol 12, 546-558, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Beta Adrenergic Receptor-Mediated Adenosine Cyclic 3',5'-Monophosphate Accumulation in the Rat Corpus Striatum

¹ Department of Pharmacology, Emory University, Atlanta, Georgia 30322

After labeling with [¹⁴C]adenine, the conversion of newly formed adenosine triphosphate to [¹⁴C]adenosine cyclic 3',5'-monophosphate ([¹⁴C]cAMP) was studied in both slices and crude mitochondrial fractions of the rat corpus striatum in the presence of a phosphodiesterase inhibitor. The observed order of potency for -hydroxylated catecholamines in stimulating [¹⁴C]cAMP accumulation in striatal slices was (-)-isoproterenol > (-)-epinephrine > (-)-norephinephrine, with EC₅₀ values (concentration resulting in 50% of maximum stimulation) of 0.03, 0.7, and 3.0 µM, respectively. In comparison, non--hydroxylated catecholamines were much less potent, with N-isopropyldopamine > dopamine (EC₅₀ = 60 µM); apomorphine was least active. Stereoselectivity was exhibited, with the (-) isomers of isoproterenol and norepinephrine being more potent than the racemic and (+) isomer, respectively. Over a wide range of concentrations, the response curves for (+)-norepinephrine and dopamine were similar. No "additive stimulatory effect" or significant enhancement of cAMP accumulation was demonstrated when dopamine was combined with maximum effective concentrations of norepinephrine or isoproterenol. Beta adrenergic antagonists, such as propranolol, MJ-1999 (sotalol), and alprenolol, were potent blockers of the dopamine-induced stimulation of cAMP formation, whereas the alpha adrenergic blocker phentolamine and the dopamine receptor antagonists chloropromazine and trifluoperazine were relatively inactive. Furthermore, low concentrations of propranolol displayed stereoselective inhibition, with the (-) isomer being the more potent antagonist of the stimulatory response to dopamine. A similar order of potency for catecholamines was exhibited in a crude mitochondrial preparation (P₂) of striatal homogenates: (±)-isoproterenol > (-)-norepinephrine > dopamine = (+)-norepinephrine. Dopamine did not augment the maximum response elicited by isoproterenol. Likewise, in striatal homogenates, the inhibitory potency of beta adrenergic antagonists contrasted markedly with the low blocking activity of trifluoperazine. Finally, in cerebral cortical slices and crude mitochondrial fractions from brain regions, including the cerebral cortex and hindbrain, which are sparsely innervated by dopaminergic terminals, a small but significant acceleration of cAMP accumulation was elicited by dopamine. Our findings in striatal slices and crude mitochondrial fractions containing synaptosomes suggest that the dopamine-induced accumulation of [¹⁴C]cAMP may not be associated with a specific dopamine receptor-coupled adenylate cyclase but may involve a beta adrenergic receptor-linked cyclase which is weakly responsive to non--hydroxylated catecholamines, such as dopamine.

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ACKNOWLEDGMENTS The author wishes to acknowledge the excellent technical assistance of Ms. Sarita Kasriel and Ms. Janice Patrick in the laboratory of Dr. J. F. Kuo.