A novel phenylaminotetralin (PAT) recognizes histamine H-1 receptors and stimulates dopamine synthesis in vivo in rat brain

A series of novel phenylaminotetralins (PATs) previously was shown to recog nize discrete binding sites that are stereoselectively labeled by [H-3]-(-) -trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene (H-2-PAT) and highly localized in catecholaminergic nerve terminal regions in guinea pig forebrain. Furthermore, certain PATs stimulate tyrosine hydroxylase an d dopamine synthesis in guinea pig and rat brain in vitro. In the current s tudies, we characterized sites labeled by [H-3]-(-)-trans-H-2-PAT and measu red effects of PATs on dopamine synthesis in vivo in rat brain. [H-3]-(-)-T rans-H-2-PAT binds saturably (B-max similar to 13 fmol/mg protein) and with high affinity (K-D similar to 0.5 nM) to a single population of sites in r at brain. The ligand binding profile of [H-3]-(-)-trans-H-2-PAT labeled sit es is very similar to histamine H-1 receptors labeled with [H-3]-mepyramine . After i.c.v. injection to rats, (+/-)-trans H-2-PAT (4-40 nmoles/kg) stim ulates dopamine synthesis (to about 180% of control levels) selectively in the limbic brain region nucleus accumbens vs. the extrapyramidal region str iatum; this effect is fully blocked by(+/-)-cis-H-2-PAT and the H-1 antagon ist triprolidine. At higher doses (> 40 nmoles/kg), the observed stimulatio n of dopamine synthesis is attenuated to control levels, likely due to acti vation of feedback mechanisms resulting from non-receptor mediated displace ment of intraneuronal dopamine. We propose that PATs represent a novel clas s of ligands for H-1 receptors that can modulate tyrosine hydroxylase activ ity and dopamine synthesis in the limbic region of mammalian forebrain. (C) 2000 Published by Elsevier Science B.V. All rights reserved.