Molecular Pharmacology, Vol 10, 933-940, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

Norepinephrine-Sensitive Systems Generating Adenosine 3',5'-Monophosphate: Increased Responses in Cerebral Cortical Slices from Reserpine-Treated Rats

¹ National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014

The magnitude of accumulations of cyclic AMP elicited by various concentrations of norepinephrine was increased by 40-60% in cerebral cortical slices obtained from Sprague-Dawley rats 2 days after the first of two daily treatments with reserpine. The enhanced response of cortical cyclic AMP-generating systems to norepinephrine developed between 5 and 48 hr and disappeared between day 9 and day 16 after reserpine. The apparent EC₅₀ of norepinephrine was not altered to a measurable extent by prior treatment with reserpine. The enhancement in the response was similar throughout a 4-90-min stimulation of slices. The response to isoproterenol or a norepinephrine-phentolamine combination was increased by 50-70%, while the response to a norepinephrine-propranolol combination was not significantly increased. This suggests that reserpine treatment may have caused a partly selective increase in the beta adrenergic component of the response to catecholamines. The response of cyclic AMP-generating systems to veratridine was not increased by reserpine, but there was about a 30% increase in the response to adenosine. The response to a combination of norepinephrine and a phosphodiesterase inhibitor, Ro 20-1724, was enhanced by about 40% in cortical slices from reserpine-treated rats, while the responses to combinations of either serotonin, dopamine, or histamine with the phosphodiesterase inhibitor were not enhanced above responses in control slices. It is proposed that the decreased availability of the neurotransmitter, norepinephrine, in reserpine-treated rats results in an enhanced concentration or responsiveness of nonrepinephrine-sensitive adenylate cyclase. Another possibility is a selective decrease in phosphodiesterase activity associated with this cyclase. The data do not permit an unambiguous choice between these alternatives.

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