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

Abstract The biosynthesis of norepinephrine occurs through a multi-enzymatic pathway that includes the enzyme dopamine-β-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 (α 1 -AR, α 2 -AR and β-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 α 1 -AR, α 2 -AR and β-AR were assayed with [ 3 H]prazosin, [ 3 H]RX21002 and [ 125 I]-iodo-pindolol autoradiography, respectively. The α 2 -AR agonist high affinity state was examined with [ 125 I]- para -iodoclonidine autoradiography and α 2 -AR functionality by α 2 -AR agonist-stimulated [ 35 S]GTPγS autoradiography. The density of α 1 -AR in Dbh −/− mice was similar to Dbh +/− mice in most brain regions, with an up-regulation in the hippocampus. Modest decreases in α 2 -AR were found in septum, hippocampus and amygdala, but these were not reflected in α 2 -AR functionality. The density of β-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.