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Starting from the sequence of the human histamine H₃ receptor (hH₃R) cDNA, we have cloned the corresponding rat cDNA. Whereas the two deduced proteins show 93.5% overall homology and differ only by five amino acid residues at the level of the transmembrane domains (TMs), some ligands displayed distinct affinities. Thioperamide and ciproxifan were about 10 fold more potent at the rat than at the human receptor, whereas FUB 349 displayed a reverse preference. Histamine, (R)α‐methylhistamine, proxyfan or clobenpropit were nearly equipotent at H₃ receptors of both species. The inverse discrimination patterns of ciproxifan and FUB 349 were partially changed by mutation of one amino acid (V122A), and fully abolished by mutation of two amino acids (A119T and V122A), in TM3 of the rH₃R located in the vicinity of Asp¹¹⁴ purported to salt‐link the ammonium group of histamine. Therefore, these two …