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 (α1-AR, α2-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 α1-AR, α2-AR and β-AR were assayed with [3H]prazosin, [3H]RX21002 and [125I]-iodo-pindolol autoradiography, respectively. The α2-AR agonist high affinity state was examined with [125I]-para-iodoclonidine autoradiography and α2-AR functionality by α2-AR agonist-stimulated [35S]GTPγS autoradiography. The density of α1-AR in Dbh−/− mice was similar to Dbh+/− mice in most brain regions, with an up-regulation in the hippocampus. Modest decreases in α2-AR were found in septum, hippocampus and amygdala, but these were not reflected in α2-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. [Copyright &y& Elsevier]