Reduced density of functional 5‐HT 1A 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‐HT 1A receptors (5‐HT 1A R) expressed in the brain by postnatal day P7 are affected and, if so, whether the 5‐HT 1A autoreceptors in the dorsal raphe are modified in the same way as the postsynaptic 5‐HT 1A R present in raphe target structures. [ 3 H]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‐HT 1A R 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‐HT 1A R 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‐HT 1A R 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‐HT 1A R 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. J. Comp. Neurol. 495:607–623, 2006. © 2006 Wiley‐Liss, Inc.