5-HYDROXYTRYPTAMINE (5-HT)(4) RECEPTORS IN POST-MORTEM HUMAN BRAIN-TISSUE - DISTRIBUTION, PHARMACOLOGY AND EFFECTS OF NEURODEGENERATIVE DISEASES

The distribution, pharmacology and effects of neurodegenerative diseas es on 5-HT4 receptors in human brain have been characterized in vitro. 2 The 5-HT4 receptor in post mortem human brain tissue was specifical ly labelled with [H-3]-GR 113808. In human putamen, this ligand labell ed a homogeneous population of sites, with an apparent affinity (-log K-d) of 10.1 and a density (B-max) of 5.73 fmol mg(-1) tissue. The pha rmacology of this site was characterized by use of a series of displac ing ligands, and the following rank order of apparent affinities (with mean +/- s.d. -log K-i values in parentheses) was generated: GR113808 (10.05 +/- 0.04)>SDZ 205,557 (8.65 +/- 0.08)>DAU 6285 (7.95 +/- 0.04) >BIMU-1 (7.81 +/- 0.06)>DAU 6215 (7.42 +/- 0.23)>tropisetron (7.39 +/- 0.23)>5-HT (7.32 +/- 1.00)>BIMU-8 (7.25 +/- 0.04)>(R)-zacopride (5.82 +/- 0.04). The Hill coefficients were not significantly different fro m unity, consistent with an interaction at a single site. A comparison of the affinities of these compounds with those obtained from guinea- pig striatum indicated no evidence of species differences. 3 The regio nal distribution of 5-HT4 receptors was assessed by determining the de nsity of binding sites for [H-3]-GR 113808. The distribution were as f ollows (with mean +/- s.d. B-max values, fmol mg(-1) tissue, in parent heses): caudate nucleus (8.7 +/- 1.5), lateral pallidum (8.6 +/- 5.5), putamen (5.7 +/- 3.0), medial pallidum (3.8 +/- 0.9), temporal cortex (2.6 +/- 0.6), hippocampus (2.4 +/- 0.8), amygdala (2.3 +/- 1.1), fro ntal cortex (1.7 +/- 0.5), cerebellar cortex (<1.0). In these studies, the affinities of GR 113808 were not significantly different. 4 The d ensity of 5-HT4 receptors selected from regions of post mortem brains of patients with Parkinson's disease, Huntington's disease and Alzheim er's disease were compared to age-matched controls. In Parkinson's dis ease, there was no significant difference between control or patient v alues (mean +/- s.d. B-max values, fmol mg(-1) tissue; putamen, contro l 4.74 +/- 0.07, patient 5.86 +/- 1.48; substantia nigra, control 4.21 +/- 2:56, patient 5.57 +/- 0.10). In Huntington's disease, there was a significant decrease in putamen (control 5.33 +/- 1.08, patient 2.68 +/- 1.08), while in Alzheimer's disease, there was a marked loss of r eceptors in hippocampus (control 2.34 +/- 0.62, patient 0.78 +/- 0.61) , in frontal cortex (control, 1.76 +/- 0.19, patient 1.30 +/- 0.22). R eceptor density in temporal cortex showed a decrease, but did not achi eve statistical significance (control 2.06 +/- 0.21, patient 1.44 +/- 0.64). 5 These data suggest a heterogeneous distribution of 5-HT4 rece ptors in human brain, with high to moderate densities in basal ganglia and limbic structures. These receptors may not be principally co-loca lized on dopaminergic cell bodies or terminals, given the lack of chan ge observed in Parkinson's disease. The loss of 5-HT4 receptors in the putamen in Huntington's disease raises the possibility of their prese nce on intrinsic striatal GABAergic or cholinergic neurones. The marke d loss of receptors in hippocampal and cortical regions in the brains from patients with Alzheimer's disease is consistent with a role for t he 5-HT4 receptor in cognitive processing.