Restoration of norepinephrine and reversal of phenotypes in mice lacking dopamine beta-hydroxylase.
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.
Thomas
S A
SA
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, USA.
Marck
B T
BT
Palmiter
R D
RD
Matsumoto
A M
AM
D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D015103:Droxidopa / Q000008:administration & dosage / Q000494:pharmacology*; D004837:Epinephrine / Q000096:biosynthesis; D006614:Hindlimb / Q000502:physiology; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D024101:Mitochondrial Proteins; D009638:Norepinephrine / Q000096:biosynthesis*; D009928:Organ Specificity; D010641:Phenotype; D011930:Reaction Time / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D000071256:Uncoupling Protein 1; D004299:Dopamine beta-Hydroxylase; D015103:Droxidopa; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine