PHARMACOLOGICAL CHARACTERIZATION AND AUTORADIOGRAPHIC LOCALIZATION OF HISTAMINE H-2 RECEPTORS IN HUMAN BRAIN IDENTIFIED WITH [I-125] IODOAMINOPOTENTIDINE

I-125-Aminopotentidine (I-125-APT), a reversible probe of high specific radioactivity and high affinity and selectivity for the H-2 receptor, was used to characterize and localize this histamine receptor subtype in human brain samples obtained at autopsy. On membranes of human caudate nucleus, specific I-125-APT binding at equilibrium revealed a single component, with a dissociation constant of 0.3 nM and maximal capacity of about 100 fmol/mg of protein. At 0.2 nM, I-125-APT specific binding, as defined with tiotidine, an H-2-receptor antagonist chemically unrelated to iodoaminopotentidine, represented 40-50% of the total. Specific I-125-APT binding was inhibited by a series of typical H-2-receptor antagonists that displayed apparent dissociation constants closely similar to cor-responding values at the reference biological system, i.e., guinea pig atrium. This indicates that the pharmacology of the H-2 receptor is the same in the human brain as on this reference system. However histamine was about 10-fold more potent in inhibiting I-125-APT binding to membranes of human brain than of guinea pig brain. I-125-APT binding was also inhibited by amitriptyline and mianserin, two antidepressant drugs, in micromolar concentrations corresponding to effective plasma concentrations of treated patients. The distribution of H-2 receptors was established autoradiographically With I-125-APT on a series of coronal sections of human brain after assessing the pharmacological specificity of the labeling. The highest density of I-125-APT sites was found in the basal ganglia, various parts of the limbic system, e.g., hippocampus or amygdaloid complex, and the cerebral cortex. H-2 receptors displayed a laminar distribution in cerebral cortex and hippocampal formation. A low density of sites was found in cerebellum as well as in hypothalamus, the brain area where all the perikarya and the largest number of axons of histaminergic neurons are found. The widespread distribution of H-2 receptors in the human brain is consistent with the alleged modulatory role of histamine mediated by this subtype of receptor.