Reduced density of functional 5-HT1A receptors in the brain, medulla and spinal cord of monoamine oxidase-A knockout mouse neonates.
Abnormally high brain 5-HT levels in monoamine oxidase-A knockout (MAO-A KO) mouse neonates raise the question of whether the distribution and density of the 5-HT1A receptors (5-HT1AR) expressed in the brain by postnatal day P7 are affected and, if so, whether the 5-HT1A autoreceptors in the dorsal raphe are modified in the same way as the postsynaptic 5-HT1AR present in raphe target structures. [3H]8-OH-DPAT binding and quantitative autoradiography were performed to answer these questions. Binding specificity was first confirmed in adult wild-type mice and rat brain sections. 5-HT1AR binding was then analyzed in four MAO-A mutant vs. five wild-type neonatal brains, from olfactory bulb to cervical cord. Among 12 structures expressing postsynaptic 5-HT1AR in wild-type neonates, the highest densities involved the retrosplenial cortex, entorhinal cortex, and septum (52-46 fmol/mg tissue); low densities occurred in the hippocampus and spinal cord (24 fmol/mg tissue); in addition, the raphe autoreceptor density was only 20 fmol/mg tissue. In mutants, the distribution of postsynaptic 5-HT1AR was unchanged, but an overall decrease in density occurred (-32% to -63%); the raphe autoreceptors decreased in mutants by at least -79%. Data are discussed with reference to the ectopic 5-HT uptake and accumulation reported to occur during the first 10 postnatal days in wild-type and MAO-A KO mice. As previously suggested to explain the raphe autoreceptor loss in 2-month-old MAO-A KO mice, the overall 5-HT1AR down-regulation in mutant pups probably results from extracellular 5-HT excess in both raphe and target structures. The greater the 5-HT excess, the more the functional receptor density decreases.
Centre National de la Recherche Scientifíque-Groupe d'Etude des Reseaux Moteurs et Université de la Méditerranée, F-13009 Marseille, France. lanoir@marseille.inserm.fr
Jeanne
J
Lanoir
Gerard
G
Hilaire
Isabelle
I
Seif
D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D008526:Medulla Oblongata / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D050486:Serotonin Plasma Membrane Transport Proteins; C493453:Slc18a2 protein, mouse; C493231:Slc6a4 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; D008995:Monoamine Oxidase