Putative σ3 sites in mammalian brain have histamine H1 receptor properties:: evidence from ligand binding and distribution studies with the novel H1 radioligand [3 H]-(-)-trans-1-phenyl-3-aminotetralin

A novel phenylaminotetralin (PAT) radioligand, [H-3]-(1R,3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphaklene ([H-3]-[-]-trans-H-2-PAT), is shown here to label a saturable (B-max = 39 +/- 6 fmol/mg protein) population of sites with high affinity (K-d = 0.13 +/- 0.03 nM) in guinea pig brain. Consistent with previous studies which showed that PATs stimulate catecholamine (dopamine) synthesis in rat striatum, autoradiographic brain receptor mapping studies here indicate that [H-3]-(-)-trans-H-2-PAT-labeled sites are highly localized in catecholaminergic nerve terminal fields in hippocampus, nucleus accumbens, and striatum in guinea pig brain. Competition binding studies with a broad range of CNS receptor-active ligands and CNS radioreceptor screening assays indicate that the pharmacological binding profile of brain [H-3]-(-)-trans-H-2-PAT sites closely resembles histamine H-1-type receptors. Comparative studies using the histamine H-1 antagonist radioligand, [H-3]mepyramine, indicate that the H-1 ligand binding profile and guinea pig brain distribution of H-1 receptors and [H-3]-(-)-trans-H-2-PAT sites are nearly identical;moreover, both sites have about 40-fold stereoselective affinity for (-)- over (+)-trans-H-2-PAT. These results are discussed in light of previous studies which suggested that PATs stimulate dopamine synthesis through interaction with a novel sigma-type (sigma(3)) receptor in rodent brain; it now appears instead that PATs represent a new class of ligands for brain histamine H-1 receptors that can be stereoselectively labeled with [H-3]-(-)-trans-H-2-PAT. (C) 1999 Published by Elsevier Science B.V. All rights reserved.