Molecular Pharmacology, Vol 20, 331-338, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Specific Desensitization of Histamine H₁ Receptor-Mediated [³H]Glycogen Hydrolysis in Brain Slices

¹ Unité de Neurobiologie, Centre Paul Broca de l’Institut National de la Santé et de la Recherche Médicale, 75014 Paris, France

In slices from mouse cerebral cortex, histamine elicits in a concentration-dependent manner the hydrolysis of [³H]glycogen previously synthesized from [³H]glucose, a response mediated by H₁ receptors. Desensitization of this glycogenolytic response occurs when slices are incubated with 50 µM histamine and is characterized by a rightward shift of the concentration-response curve (EC₅₀ = 32 ± 1 µM instead of 4 ± 1 µM) without significant change in the maximal glycogenolysis. Desensitization occurs with a half-time of about 20 min, and the initial responsiveness is gradually recovered within 1 hr. Recovery is not impaired in the presence of cycloheximide, a protein synthesis inhibitor. Desensitization to the glycogenolytic action of histamine seems to be a selective process: (a) it results from stimulation of H₁ receptors, since 2-thiazolylethylamine, an H₁-receptor agonist (but not dimaprit, an H₂-receptor agonist) shares the desensitizing action of histamine; (b) only the glycogenolytic response to histamine is desensitized, whereas responsiveness to other glycogenolytic agents (noradrenaline, serotonin, adenosine, dibutyryl cyclic AMP) is not modified. Following exposure of slices to histamine, the binding of [³H]mepyramine to H₁ receptors is significantly modified. The change consists of a 20% decrease in the B_max of the [³H]antihistamine without significant change in either its K_d or the K_i of histamine.