Mapping of serotonin 5‐HT 4 receptor mRNA and ligand binding sites in the post‐mortem human brain

Mapping of serotonin 5‐HT 4 receptor mRNA and ligand binding sites in the post‐mortem human... The anatomical localization of 5‐HT4 receptor mRNA and 5‐HT4 receptor protein was examined in sections of post‐mortem human brain by in situ hybridization histochemistry and radioligand receptor autoradiography. In the in situ hybridization study, the highest levels of 5‐HT4 receptor mRNA were found in caudate nucleus, putamen, nucleus accumbens, and in the hippocampal formation. No 5‐HT4 receptor mRNA was detected in globus pallidus and substantia nigra. For receptor autoradiography, two new and highly selective radioligands were compared: (3H)prucalopride, which preferentially labels the G‐protein coupled fraction of receptors, and (3H)R116712, which labels the entire receptor population at subnanomolar concentrations. (3H)Prucalopride and (3H)R116712 binding was performed on human brain hemisphere sections. The highest densities for both radioligands were found in the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus, substantia nigra). Moderate to low densities were detected in the hippocampal formation and in the cortical mantle. Mismatches between 5‐HT4 receptor mRNA and binding sites in the globus pallidus and the substantia nigra suggested that the binding sites may be localized on axonal projections originating from the striatum. To compare densities of binding sites, concentration binding curves with (3H)prucalopride, (3H)R116712 and (3H)GR113808 were performed on membranes from homogenates of several human brain regions. Comparison of Bmax‐values obtained with (3H)prucalopride and (3H)R116712 indicated that the G‐protein coupled fraction of 5‐HT4 receptors in the substantia nigra was exceptionally high (54%) in comparison with percentages (16–27%) found in the frontal cortex, the striatum and the hippocampus. Such a high percentage (40%) of (3H)prucalopride vs. (3H)R116712 binding was also observed in the substantia nigra in the receptor autoradiography experiments. The (3H)prucalopride binding was GppNHp‐sensitive, whereas (3H)R116712 and (3H)GR113808 was not. These data indicate that in the substantia nigra 5‐HT4 receptors are more strongly coupled to their signal transduction pathway than in other brain regions. Synapse 36:35–46, 2000. © 2000 Wiley‐Liss, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Synapse Wiley

Mapping of serotonin 5‐HT 4 receptor mRNA and ligand binding sites in the post‐mortem human brain

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Publisher
Wiley
Copyright
Copyright © 2000 Wiley‐Liss, Inc.
ISSN
0887-4476
eISSN
1098-2396
DOI
10.1002/(SICI)1098-2396(200004)36:1<35::AID-SYN4>3.0.CO;2-Y
pmid
10700024
Publisher site
See Article on Publisher Site

Abstract

The anatomical localization of 5‐HT4 receptor mRNA and 5‐HT4 receptor protein was examined in sections of post‐mortem human brain by in situ hybridization histochemistry and radioligand receptor autoradiography. In the in situ hybridization study, the highest levels of 5‐HT4 receptor mRNA were found in caudate nucleus, putamen, nucleus accumbens, and in the hippocampal formation. No 5‐HT4 receptor mRNA was detected in globus pallidus and substantia nigra. For receptor autoradiography, two new and highly selective radioligands were compared: (3H)prucalopride, which preferentially labels the G‐protein coupled fraction of receptors, and (3H)R116712, which labels the entire receptor population at subnanomolar concentrations. (3H)Prucalopride and (3H)R116712 binding was performed on human brain hemisphere sections. The highest densities for both radioligands were found in the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus, substantia nigra). Moderate to low densities were detected in the hippocampal formation and in the cortical mantle. Mismatches between 5‐HT4 receptor mRNA and binding sites in the globus pallidus and the substantia nigra suggested that the binding sites may be localized on axonal projections originating from the striatum. To compare densities of binding sites, concentration binding curves with (3H)prucalopride, (3H)R116712 and (3H)GR113808 were performed on membranes from homogenates of several human brain regions. Comparison of Bmax‐values obtained with (3H)prucalopride and (3H)R116712 indicated that the G‐protein coupled fraction of 5‐HT4 receptors in the substantia nigra was exceptionally high (54%) in comparison with percentages (16–27%) found in the frontal cortex, the striatum and the hippocampus. Such a high percentage (40%) of (3H)prucalopride vs. (3H)R116712 binding was also observed in the substantia nigra in the receptor autoradiography experiments. The (3H)prucalopride binding was GppNHp‐sensitive, whereas (3H)R116712 and (3H)GR113808 was not. These data indicate that in the substantia nigra 5‐HT4 receptors are more strongly coupled to their signal transduction pathway than in other brain regions. Synapse 36:35–46, 2000. © 2000 Wiley‐Liss, Inc.

Journal

SynapseWiley

Published: Apr 1, 2000

References

  • Lesion study of the distribution of serotonin 5‐HT 4 receptors in rat basal ganglia and hippocampus
    Compan, Compan; Daszuta, Daszuta; Salin, Salin; Sebben, Sebben; Bockaert, Bockaert; Dumuis, Dumuis
  • GR113808: a novel, selective antagonist with high affinity at the 5‐HT 4 receptor
    Gale, Gale; Grossman, Grossman; Whitehead, Whitehead; Oxford, Oxford; Bunce, Bunce; Humphrey, Humphrey
  • 5‐HT receptor classification and nomenclature: towards a harmonization with the human genome
    Hoyer, Hoyer; Martin, Martin
  • BIMU1 increases associative memory in rats by activating 5‐HT 4 receptors
    Marchetti‐Gauthier, Marchetti‐Gauthier; Roman, Roman; Dumuis, Dumuis; Bockaert, Bockaert; Soumireu‐Mourat, Soumireu‐Mourat
  • Effects of 5‐HT 4 receptor agonists and antagonists in learning
    Meneses, Meneses; Hong, Hong
  • 5‐Hydroxytryptamine (5‐HT) 4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases
    Reynolds, Reynolds; Mason, Mason; Meldrum, Meldrum; De Keczer, De Keczer; Parnes, Parnes; Eglen, Eglen; Wong, Wong

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