Analysis of brain adrenergic receptors in dopamine-β-hydroxylase knockout mice

The biosynthesis of norepinephrine occurs through a multi-enzymatic pathway that includes the enzyme dopamine-beta-hydroxylase (DBH). Mice with a homozygous deletion of DBH (Dbh-/-) have a selective and complete absence of norepinephrine. The purpose of this study was to assess the expression of alpha-1, alpha-2 and beta adrenergic receptors (alpha(1)-AR, alpha(2)-AR and beta-AR) in the postnatal absence of norepinephrine by comparing noradrenergic receptors in Dbh-/- mice with those in Dbh heterozygotes (Dbh+/-), which have normal levels of norepinephrine throughout life. The densities of alpha(1)-AR, alpha(2)-AR and beta-AR were assayed with [H-3]prazosin, [H-3]RX21002 and [I-125]-iodo-pindolol autoradiography, respectively. The alpha(2)-AR agonist high affinity state was examined with [I-125]-paraiodoclonidine autoradiography and alpha(2)-AR functionality by alpha(2)-AR agonist-stimulated [S-35] GTP gamma S autoradiography. The density of alpha(1)-AR in Dbh-/- mice was similar to Dbh+/- mice in most brain regions, with an up-regulation in the hippocampus. Modest decreases in alpha(2)-AR were found in septum, hippocampus and amygdala, but these were not reflected in alpha(2)-AR functionality. The density of beta-AR was up-regulated to varying degrees in many brain regions of Dbh-/- mice compared to the heterozygotes. These findings indicate that regulation of noradrenergic receptors by endogenous norepinephrine depends on receptor type and neuroanatomical region. (c) 2006 Elsevier B.V. All rights reserved.