Molecular Pharmacology, Vol 13, 679-689, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Altered Responsiveness of Cerebral Beta Adrenoceptors Assessed by Adenosine Cyclic 3',5'-Monophosphate Formation and [³H]Propranolol Binding

¹ Department of Pharmacology and Therapeutics, School of Medicine, University of Leicester, Leicester, LE1 7RH, England

The chronic treatment of neonate chicks with reserpine on 6-hydroxydopamine severely depleted cerebral catecholamines and resulted in an increased responsiveness of beta adrenoceptor-mediated cyclic 3',5'-AMP formation in the cerebral hemispheres both in vivo and in slices in vitro. Conversely, treatment of chicks with isoproterenol suspended in glycerol trioleate, to effect slow release of the catecholamine, induced marked densensitization of the cyclic AMP response. The enhanced response to isoproterenol was already observed in vivo 12 hr after a single injection of reserpine and was maintained for at least 72 hr. Densensitization was fully developed 3-6 hr after chronic isoproterenol, but normal responses were again observed by 18 hr. The altered responsiveness was specific for beta adrenoceptor agonists both in vivo and in cerebral slices in vitro. The responses to histamine and adenosine were not significantly altered. However, incubation of slices in the presence of the phosphodiesterase inhibitor Ro 20-1724 at least partially reversed the hyporesponsiveness induced by chronic isoproterenol without influencing the enhanced responses seen in reserpine-treated chicks. On the other hand, the activity of adenylate cyclase and phosphodiesterase in homogenates of cerebral hemispheres was similar in all groups. Despite an increased responsiveness of beta adrenoceptor-mediated cyclic AMP formation after reserpine, there was no change in the characteristics of binding of the specific ligand [³H]propranolol to cerebral membranes from these animals. However, the densensitized cyclic AMP response induced by chronic isoproterenol was accompanied by a 30% reduction in the maximum binding of [³H]propranolol but not in the binding affinity of the ligand to cerebral membranes. It is proposed that cerebral beta adrenoceptors can adjust their responsiveness in relation to the availability of catecholamines, and possible mechanisms are discussed.

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ACKNOWLEDGMENTS I would like to thank Mr. J. Anson for excellent technical assistance, and Miss J. Bell for preparing the manuscript.

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