Antidepressant Activity Requires Norepinephrine

Abstract

Cryan et al. used mice deficient for the norepinephrine (and epinephrine) biosynthetic enzyme dopamine β-hydroxylase ( Dbh —/— ) to determine that the acute behavioral effects of different classes of antidepressants were dependent on norepinephrine and not only on changes in serotonergic or dopaminergic signaling. Drugs that were not selective but inhibited the reuptake or metabolism of serotonin, dopamine, and norepinephrine were effective in heterozygous littermates, but not in Dbh —/— mice, at decreasing immobility in the tail suspension test, an assay for the acute effects of antidepressant drugs. Two of the three drugs in the serotonin selective reuptake class were not effective in decreasing immobility in the tail suspension test 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 norepinephrine by administration of the precursor L- threo -3,4-dihydroxyphenylserine (L-DOPS) restored responsiveness to norepinephrine selective reuptake inhibitors and the serotonin selective reuptake inhibitors. Thus, most antidepressants appear to have a requirement for noradrenergic signaling, with the exception of citalopram, which appears to bypass this requirement. J. F. Cryan, O. F. O'Leary, S.-H. Jin, J. C. Friedland, M. Ouyang, B. R. Hirsch, M. E. Page, A. Dalvi, S. A. Thomas, I. Lucki, Norepinephrine-deficient mice lack responses to antidepressant drugs, including serotonin reuptake inhibitors. Proc. Natl. Acad. Sci. U.S.A. 101 , 8186-8191 (2004). [Abstract] [Full Text]