Molecular Pharmacology, Vol 14, 971-982, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Pharmacological Characterization of Histamine Receptors Mediating the Stimulation of Cyclic AMP Accumulation in Slices from Guinea-Pig Hippocampus

¹ Unité 109 de Neurobiologie, Centre Paul Broca de l’I. N. S. E. R. M., 2ter rue d’Alesia, 75014 Paris, France

A histamine-sensitive adenylate cyclase presenting characteristics very similar to typical H₂-receptors has recently been demonstrated in cell-free brain preparations, whereas the stimulation of cyclic AMP accumulation elicited by histamine in cerebral slices has been postulated to involve both H₁- and H₂-receptors. We have reinvestigated the pharmacological properties of histamine receptors mediating the stimulation of cyclic AMP in guinea-pig hippocampal slices by determining the relative potencies of several agonists and the apparent affinities of antagonists. Metiamide, a H₂-blocker, antagonizes in a competitive manner the stimulation elicited by histamine (or 2-thiazolylethylamine, a predominantly H₁-agonist) with a pA₂ value of 6, corresponding to an interaction with a single population of typical H₂-receptors. The relative potencies of two H₂-agonists (dimaprit and 4-methylhistamine) are consistent with this view. However other data suggest the involvement of an heterogeneous population of histamine receptors. First, the relative potencies of two H₁-agonists (2-thiazolylethylamine and 2-methylhistamine) in hippocampal slices are intermediate between corresponding values on homogeneous populations of H₁- and H₂-receptors, respectively. Furthermore in the presence of moderate concentrations (5 nM to 0.1 µM) of mepyramine, an H₁-antagonist, the response to histamine is modified in a complex fashion: the responses to histamine in low concentrations remain unaltered whereas those to the amine in concentrations above 10 µM are competitively antagonized. Analysis of these data by Schild plot or by a computer program reveals two components in the response to histamine: a first one (insensitive to mepyramine) with an EC₅₀ of 6µM and a second one with an EC₅₀ of 14 µM for the amine (antagonized by mepyramine with a pA₂ of 8.2). The participation of each component to the maximal response is approximately 50%. In addition, a series of H₁-antagonists inhibit the response to 100 µM histamine with apparent K_B 5 toward the second component which appear to be in the same range as those toward typical H₁-receptors. Furthermore the supramaximal response to dimaprit, a pure H₂-agonist, is progressively elevated in the presence of 2-thiazolylethylamine, a predominantly H₁-agonist, in increasing concentrations. In these conditions the relative potency of 2-thiazolylethylamine becomes comparable with the value for typical H₁-receptors. This additive response is blocked by 0.1 µM mepyramine while the response to dimaprit alone is not affected. It is concluded that the response to histamine in brain slices involves the stimulation of both typical H₂-receptors and receptors closely similar to (or identical with) H₁-receptors, which appear to be activated in a sequential manner.

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