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PNAS 101 (21): 8186-8191

Copyright © 2004 by the National Academy of Sciences.


Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors

John F. Cryan * {dagger}, Olivia F. O'Leary {ddagger}, §, Sung-Ha Jin {ddagger}, Julie C. Friedland {ddagger}, Ming Ouyang {ddagger}, Bradford R. Hirsch {ddagger}, Michelle E. Page * ¶, Ashutosh Dalvi *, Steven A. Thomas {ddagger}, and Irwin Lucki *, {ddagger}, ||

Departments of *Psychiatry and {ddagger}Pharmacology, University of Pennsylvania, Philadelphia, PA 19104; and §Department of Pharmacology, National University of Ireland, Galway, Ireland

Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved April 13, 2004

Received for publication February 17, 2004.

Abstract: Mice unable to synthesize norepinephrine (NE) and epinephrine due to targeted disruption of the dopamine {beta}-hydroxylase gene, Dbh, were used to critically test roles for NE in mediating acute behavioral changes elicited by different classes of antidepressants. To this end, we used the tail suspension test, one of the most widely used paradigms for assessing antidepressant activity and depression-related behaviors in normal and genetically modified mice. Dbh–/– mice failed to respond to the behavioral effects of various antidepressants, including the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion, even though they did not differ in baseline immobility from Dbh+/– mice, which have normal levels of NE. Surprisingly, the effects of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, and paroxetine were also absent or severely attenuated in the Dbh–/– mice. In contrast, citalopram (the most selective SSRI) was equally effective at reducing immobility in mice with and without NE. Restoration of NE by using L-threo-3,4-dihydroxyphenylserine reinstated the behavioral effects of both desipramine and paroxetine in Dbh–/– mice, thus demonstrating that the reduced sensitivity to antidepressants is related to NE function, as opposed to developmental abnormalities resulting from chronic NE deficiency. Microdialysis studies demonstrated that the ability of fluoxetine to increase hippocampal serotonin was blocked in Dbh–/– mice, whereas citalopram's effect was only partially attenuated. These data show that NE plays an important role in mediating acute behavioral and neurochemical actions of many antidepressants, including most SSRIs.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: NE, norepinephrine; NET, NE transporter; 5-HT, serotonin; SERT, 5-HT transporter; DA, dopamine; DBH, DA{beta}-hydroxylase; SSRI, selective 5-HT reuptake inhibitor; L-DOPS, L-threo-3,4-dihydroxyphenylserine; TST, tail suspension test; FST, forced swim test.

{dagger} Present address: Neuroscience Disease Area, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.

Present address: Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129.

|| To whom correspondence should be addressed at: Department of Psychiatry, University of Pennsylvania, 538A Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104-6140. E-mail: lucki{at}

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