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Restoration of Norepinephrine and Reversal of Phenotypes in Mice Lacking Dopamine β‐Hydroxylase
Author(s) -
Thomas Steven A.,
Marck Brett T.,
Palmiter Richard D.,
Matsumoto Alvin M.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.70062468.x
Subject(s) - dopamine , medicine , endocrinology , norepinephrine , catecholamine , epinephrine , aromatic l amino acid decarboxylase , midbrain , tyrosine hydroxylase , carbidopa , biology , chemistry , levodopa , central nervous system , parkinson's disease , disease
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.