Cerebral 5-HT2A receptor binding, but not mGluR2, is increased in tryptophan hydroxylase 2 decrease-of-function mice

TY - JOUR

T1 - Cerebral 5-HT2A receptor binding, but not mGluR2, is increased in tryptophan hydroxylase 2 decrease-of-function mice

AU - Jørgensen, Christinna Vangsgaard

AU - Jacobsen, Jacob P

AU - Caron, Marc G

AU - Klein, Anders Bue

AU - Knudsen, Gitte M

AU - Mikkelsen, Jens D

N1 - Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

PY - 2013/10/25

Y1 - 2013/10/25

N2 - 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.

AB - 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.

KW - Amino Acids

KW - Animals

KW - Brain

KW - Gene Knock-In Techniques

KW - Mice

KW - Mice, Transgenic

KW - Radioligand Assay

KW - Receptor, Serotonin, 5-HT2A

KW - Receptors, Metabotropic Glutamate

KW - Tryptophan Hydroxylase

KW - Up-Regulation

KW - Xanthenes

U2 - 10.1016/j.neulet.2013.08.073

DO - 10.1016/j.neulet.2013.08.073

M3 - Journal article

C2 - 24055299

SN - 0304-3940

VL - 555

SP - 118

EP - 122

JO - Neuroscience Letters

JF - Neuroscience Letters

ER -