Cerebral 5-HT2A receptor binding, but not mGluR2, is increased in tryptophan hydroxylase 2 decrease-of-function mice.
Transgenic mice with a knock-in (KI) of a tryptophan hydroxylase 2 (Tph2) R439H mutation, analogous to the Tph2 R441H single-nucleotide polymorphism originally identified in a late life depression cohort, have markedly reduced levels of 5-hydroxytryptamine (5-HT). These Tph2KI mice are therefore interesting as a putative translational model of low endogenous 5-HT function that allows for assessment of adaptive changes in different anatomical regions. Here, we determined 5-HT2A receptor binding in several brain regions using in vitro receptor autoradiography and two different radioligands. When using the 5-HT2A receptor selective antagonist radioligand (3)H-MDL100907, we found higher binding in the prefrontal cortex (10%, P=0.009), the striatum (26%, P=0.005), and the substantia nigra (21%, P=0.027). The increase was confirmed in the same regions with the 5-HT2A/C receptor agonist, (3)H-CIMBI-36 (2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine). 5-HT2A receptors establish heteromeric receptor complexes with metabotropic glutamate 2 receptors (mGluR2), but binding levels of the mGluR2/3 ligand (3)H-LY341495 were unaltered in brain areas with increased 5-HT2A receptor levels. These data show that in distinct anatomical regions, 5-HT2A receptor binding sites are up-regulated in 5-HT deficient mice, and this increase is not associated with changes in mGluR2 binding.
Neurobiology Research Unit, University Hospital Rigshospitalet, Copenhagen, Denmark.
Christinna V
CV
Jørgensen
Jacob P
JP
Jacobsen
Marc G
MG
Caron
Anders B
AB
Klein
Gitte M
GM
Knudsen
Jens D
JD
Mikkelsen
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D051379:Mice; D008822:Mice, Transgenic; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000235:genetics*; D015854:Up-Regulation; D014966:Xanthenes / Q000378:metabolism
D000596:Amino Acids; C114624:LY 341495; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase
Autoradiography; Frontal cortex; Rat; Receptor; Serotonin; Tryptophan hydroxylase