Restoration of Norepinephrine and Reversal of Phenotypes in Mice Lacking Dopamine β-Hydroxylase |
| |
Authors: | Steven A. Thomas Brett T. Marck Richard D. Palmiter Alvin M. Matsumoto |
| |
Affiliation: | Howard Hughes Medical Institute and Department of Biochemistry, and; Geriatric Research Education and Clinical Center, V.A. Puget Sound Health Care System, and Department of Medicine, University of Washington, Seattle, Washington, U.S.A. |
| |
Abstract: | Abstract: Mice with a targeted disruption of the dopamine β-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 ∼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 β-hydroxylase-deficient mice are all reversed by DOPS injection. |
| |
Keywords: | Norepinephrine Epinephrine Dopamine Dihydroxyphenylserine Dopamine β-hydroxylase Mice |
|
|