Characterization of the 5-hydroxytryptamine1a receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes

M De Vivo and S Maayani

The inhibition of forskolin-stimulated adenylate cyclase activity by 5- hydroxytryptamine (5-HT) receptor agonists was measured in guinea pig and rat hippocampal membranes. The results were consistent with the inhibition being mediated by a single, homogeneous population of receptors. In guinea pig hippocampal membranes 8-hydroxy-2-(di-n- propylamino)tetralin, d-lysergic acid diethylamide, 5-HT and buspirone were potent in inhibiting forskolin-stimulated adenylate cyclase activity, with EC50 values of 18, 24, 53 and 146 nM, respectively. Spiperone (Kb = 26 nM) and methiothepin (Kb = 13 nM) were potent competitive antagonists at this receptor whereas ketanserin, a high affinity 5-HT2 receptor ligand, and ICS 205-930, a high affinity peripheral neuronal (M) receptor ligand, were not. In rat hippocampal membranes, 8-hydroxy-2-(di-n-propylamino)tetralin, d-lysergic acid diethylamide, 5-HT and buspirone were potent agonists and exhibited the same rank order of potency as in guinea pig hippocampal membranes. The maximal percentage of inhibition by buspirone was significantly less than the maximal percentage of inhibition by 5-HT in rat membranes, suggesting that it is a partial agonist at this receptor, with an intrinsic activity relative to 5-HT of 0.5. The concentration-response data show that the inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes is mediated by a receptor with the characteristics of the 5-HT1A binding site. We propose that the inhibition of adenylate cyclase activity is a functional correlate of this binding site. This response is suitable for measuring activities and affinities of drugs acting at 5-HT1A receptors.

Volume 238, Issue 1, pp. 248-253, 07/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics

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