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

A novel phenylaminotetralin (PAT) radioligand, [ 3 H ]-(1R,3S)-(−)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene ([ 3 H ]-[−]-trans-H2-PAT), is shown here to label a saturable (Bmax=39±6 fmol/mg protein) population of sites with high affinity (Kd=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 [ 3 H ]-(−)-trans-H2-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 [ 3 H ]-(−)-trans-H2-PAT sites closely resembles histamine H1-type receptors. Comparative studies using the histamine H1 antagonist radioligand, [ 3 H ]mepyramine, indicate that the H1 ligand binding profile and guinea pig brain distribution of H1 receptors and [ 3 H ]-(−)-trans-H2-PAT sites are nearly identical; moreover, both sites have about 40-fold stereoselective affinity for (−)- over (+)-trans-H2-PAT. These results are discussed in light of previous studies which suggested that PATs stimulate dopamine synthesis through interaction with a novel sigma-type (σ3) receptor in rodent brain; it now appears instead that PATs represent a new class of ligands for brain histamine H1 receptors that can be stereoselectively labeled with [ 3 H ]-(−)-trans-H2-PAT.