Restoration of norepinephrine and reversal of phenotypes in mice lacking dopamine beta-hydroxylase

J Neurochem. 1998 Jun;70(6):2468-76. doi: 10.1046/j.1471-4159.1998.70062468.x.


Mice with a targeted disruption of the dopamine beta-hydroxylase (DBH) gene are unable to synthesize norepinephrine (NE) and epinephrine. These mice have elevated levels of dopamine in most tissues, although the levels are only a fraction of those normally found for NE. It is noteworthy that NE can be restored to normal levels in many tissues after a single injection of the synthetic amino acid precursor of NE, L-threo-3,4-dihydroxyphenylserine (DOPS). In other tissues, NE can be restored to normal levels after multiple injections of DOPS, whereas in the midbrain and cerebellum, restoration of NE is limited to 25-30% of normal. NE levels typically peak approximately 5 h after DOPS administration and are undetectable by 48 h. Epinephrine levels are more difficult to restore. The elevated levels of dopamine fall modestly after injection of DOPS. S(-)-Carbidopa, which does not cross the blood-brain barrier, inhibits aromatic L-amino acid decarboxylase and effectively prevents restoration of NE by DOPS in the periphery, while allowing restoration in the CNS. Ptosis and reductions in male fertility, hind-limb extension, postdecapitation convulsions, and uncoupling protein expression in dopamine beta-hydroxylase-deficient mice are all reversed by DOPS injection.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain / metabolism
  • Carrier Proteins / biosynthesis
  • Dopamine / metabolism
  • Dopamine beta-Hydroxylase / deficiency*
  • Dose-Response Relationship, Drug
  • Droxidopa / administration & dosage
  • Droxidopa / pharmacology*
  • Epinephrine / biosynthesis
  • Hindlimb / physiology
  • Ion Channels
  • Male
  • Membrane Proteins / biosynthesis
  • Mice
  • Mice, Inbred Strains
  • Mice, Mutant Strains
  • Mitochondrial Proteins
  • Norepinephrine / biosynthesis*
  • Organ Specificity
  • Phenotype
  • Reaction Time / drug effects
  • Reflex / drug effects
  • Uncoupling Protein 1


  • Carrier Proteins
  • Ion Channels
  • Membrane Proteins
  • Mitochondrial Proteins
  • Uncoupling Protein 1
  • Dopamine beta-Hydroxylase
  • Droxidopa
  • Dopamine
  • Norepinephrine
  • Epinephrine