Molecular Pharmacology, Vol 18, 1-10, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Characterization of the High-Affinity Binding Sites of [³H]Histamine in Rat Brain

¹ Unité 109 de Neurobiologie, Centre Paul Broca de l'INSERM, 2ter, rue d'Alésia 75014, Paris, France

[³H]histamine binds reversibly, in a saturable manner and with high affinity, to membranes from rat brain. Both kinetic data and saturation measured at equilibrium lead to a K_D value of about 7 nM. Guanylnucleotides specifically reduce the maximal binding capacity by 35% without changing the affinity. The binding is not significantly affected by a variety of neurotransmitters. The possibility that these binding sites represent histamine receptors has been assessed. They are not associated with storage or transport systems in histaminergic neurons in view of their subcellular distribution (they are not significantly associated with synaptic vesicles) and their persistence following interruption of histaminergic pathways. [³H]Histamine binding sites are not related to histamine-N-methyltransferase, the main catabolizing enzyme for brain histamine: they differ as judged from their regional distributions (measured on membrane fractions), their subcellular distributions, and their sensitivity to a variety of inhibitory agents. That these binding sites represent postsynaptic histamine receptors is indicated by a variety of data: (i) both their heterogeneous regional distribution as well as their postnatal increase parallel those of presynaptic markers of histaminergic neurons; (ii) subfractions containing synaptic membranes are highly enriched in these binding sites; (iii) their number is half-decreased after kainate-induced degeneration of neuronal perikarya in the striatum; (iv) they are increased (+ 24%) in striatum following chronic interruption of histaminergic inputs, a feature possibly reflecting the development of "denervation hypersensitivity" of histamine receptors. The pharmacological specificity of [³H]histamine binding sites does not correspond to that of histamine receptors of either the H₁ or the H₂ type: histamine agonists are effective inhibitors of the binding but their potencies do not parallel their biological activities on either class of receptors; furthermore H1 or H2 antihistamines are only weak inhibitors. The possibility that the high-affinity [³H]histamine binding is associated with a class of histamine receptors distinct from H₁ and H₂ receptors or to a modified conformational state of the latters is discussed.

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