Molecular Pharmacology, Vol 14, 11-23, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Postsynaptic Serotonin-Sensitive Adenylate Cyclase in the Central Nervous System

II. Comparison with Dopamine-and Isoproterenol-Sensitive Adenylate Cyclases in Rat Brain

¹ Laboratoire de Physiologie Cellulaire and Groupe NB, Institut National de la Santé et de la Recherche Médicale U114, Collège de France, 75231 Paris, France

Serotonin and dopamine stimulate distinct postsynaptic sensitive adenylate cyclases in homogenates of various brain areas in newborn rats [Enjalbert, A., Bourgoin, S., Hamon, M., Adrien, J. & Bockaert, J. (1978) Mol. Pharmacol., 14, 000-000]. However, maximal effects of dopamine and serotonin on the adenylate cyclase activity in the striatum and the hypothalamus were not strictly additive. In fact, in striatum serotonin inhibited the dopamine-sensitive adenylate cyclase noncompetitively. Conversely, the maximal effects of serotonin and l-isoproterenol (a pure beta adrenergic agonist) on adenylate cyclase activity in homogenates of the cerebral cortex were strictly additive. Classical serotoninergic agonists [D-lysergic acid diethylamide (LSD), bufotenine, 5-methoxy-N,N-dimethyltryptamine] activated the adenylate cyclase in collicular homogenates. All but LSD were ineffective on the beta adrenergic-sensitive adenylate cyclase in C6 glioma cells. The antagonists tested were not specific for the serotoninergic or the dopaminergic receptors. Neuroleptics (clozapine, thioridazine, chlorpromazine, fluphenazine, and haloperidol) and classical serotoninergic antagonists (methiothepin, cyproheptadine, cinanserin, mianserin, and methergoline) interacted with both dopaminergic and serotoninergic receptors but not with beta adrenergic receptors. All these antagonists were more potent toward the dopaminethan the serotonin-sensitive adenylate cyclase. The drugs inhibited the dopamine-sensitive adenylate cyclase in a competitive manner. Methergoline was the only drug that competitively inhibited the serotonin-sensitive adenylate cyclase. The other classical serotoninergic antagonists, as well as the neuroleptics, inhibited the serotonin-sensitive enzyme by decreasing both its apparent affinity for serotonin and its maximal activity. The serotoninergic and dopaminergic receptors may exist in agonist and antagonist forms. Our results suggest that the structures of their antagonist forms may be closely related.

Note:
ACKNOWLEDGMENTS We thank the pharmaceutical companies for generous gifts of drugs, and Dr. J. Glowinski for many stimulating discussions during the preparation of the manuscript.