Histamine H₁ receptors in human brain labelled with [³H]Doxepin

Doxepin, a tricyclic antidepressant, is one of the most potent histamine H₁ antagonists. Therefore, the binding of [³H]doxepin to human brain membranes was examined. Scatchard analysis revealed two distinct binding sites. The high-affinity binding site with a dissociation constant (K_D ± S.E.M.) of 3.1 ± 0.3 × 10^-10M was pharmacologically identified as histamine H₁ receptors. Dissociation curves at low concentrations of [³H]doxepin were biphasic, suggesting several possibilities about the interaction between [³H]doxepin and histamine H₁ receptors. Tetracyclic antidepressants, mianserin and maprotiline, were very potent, with K_Ds of 3.6 ± 0.7 × 10^-10M and 7.9 ± 0.5 × 10^-10M, respectively. Mequitazine, a new antihistamine with a weak sedative effect, had a K_D of 5.8 ± 0.8 × 10^-9, making it ten times as potent as the classic antihistamine diphenyhydramine. The highest binding of [³H]doxepin to histamine H₁ receptors was found in cerebral neocortex and the limbic system. The distribution of histamine H₁ receptors in human central nervous system did not correlate with the previously reported distributions in rat brain and guinea pig brain determined by [³H]doxepin binding.