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Norepinephrine and Antidepressants

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Science  11 Jun 2004:
Vol. 304, Issue 5677, pp. 1569
DOI: 10.1126/science.304.5677.1569c

It is important to understand the role of various neurotransmitter pathways in the efficacy of antidepressants. Cryan et al. studied mice deficient for the norepinephrine (and epinephrine) biosynthetic enzyme dopamine β-hydroxylase (Dbh−/−). The acute behavioral effects of different classes of antidepressants were dependent on norepinephrine as well as on the known changes in serotonergic or dopaminergic signaling. Drugs that were not selective for a specific neurotransmitter and inhibited the reuptake or metabolism of serotonin, dopamine, and norepinephrine were effective in heterozygous littermates, but not in Dbh−/− mice, in an assay for the acute effects of antidepressant drugs. Two of the three drugs in the serotonin selective reuptake class were not effective in Dbh−/− mice. Only citalopram, which is the most selective and does not increase norepinephrine concentrations in vivo, was effective in the Dbh−/− mice. Restoration of norephinephrine by administration of a metabolic precursor restored responsiveness to each of the antidepressants tested. Thus, most antidepressants appear to have a requirement for noradrenergic signaling, with the exception of citalopram. — NG

Proc. Natl. Acad. Sci. U.S.A. 101, 8186 (2004).

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