5‐Hydroxytryptamine (5‐HT)<sub>4</sub> receptors in <i>post mortem</i> human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases (1995)

1. The distribution, pharmacology and effects of neurodegenerative diseases on 5-HT4 receptors in human brain have been characterized in vitro. 2. The 5-HT4 receptor in post mortem human brain tissue was specifically labelled with [3H]-GR 113808. In human putamen, this ligand labelled a homogeneous population of sites, with an apparent affinity (-log Kd) of 10.1 and a density (Bmax) of 5.73 fmol mg-1 tissue. The pharmacology of this site was characterized by use of a series of displacing ligands, and the following rank order of apparent affinities (with mean +/- s.d. -log Ki 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 from 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 regional distribution of 5-HT4 receptors was assessed by determining the density of binding sites for [3H]-GR 113808. The distribution were as follows (with mean +/- s.d. Bmax values, fmol mg-1 tissue, in parentheses): 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), frontal cortex (1.7 +/- 0.5), cerebellar cortex (<1.0). In these studies, the affinities of GR 113808 were not significantly different.4. The density of 5-HT4 receptors selected from regions of post mortem brains of patients with Parkinson's disease, Huntington's disease and Alzheimer's disease were compared to age-matched controls. In Parkinson's disease, there was no significant difference between control or patient values(mean +/- s.d. Bmax values, fmol mg-1 tissue; putamen, control 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 receptors 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). Receptor density in temporal cortex showed a decrease, but did not achieve statistical significance (control 2.06 +/- 0.21, patient 1.44 +/- 0.64).5. These data suggest a heterogeneous distribution of 5-HT4 receptors in human brain, with high to moderate densities in basal ganglia and limbic structures. These receptors may not be principally co-localized on dopaminergic cell bodies or terminals, given the lack of change observed in Parkinson's disease. The loss of 5-HT4 receptors in the putamen in Huntington's disease raises the possibility of their presence on intrinsic striatal GABAergic or cholinergic neurones. The marked loss of receptors in hippocampal and cortical regions in the brains from patients with Alzheimer's disease is consistent with a role for the 5-HT4 receptor in cognitive processing.