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

doi:10.1073/pnas.0401080101

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

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

Departments of ^*Psychiatry and 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 epinephrinedue to targeted disruption of the dopamine ${beta}$ -hydroxylase gene,Dbh, were used to critically test roles for NE in mediatingacute behavioral changes elicited by different classes of antidepressants.To this end, we used the tail suspension test, one of the mostwidely used paradigms for assessing antidepressant activityand depression-related behaviors in normal and genetically modifiedmice. Dbh^–/– mice failed to respond to the behavioraleffects of various antidepressants, including the NE reuptakeinhibitors desipramine and reboxetine, the monoamine oxidaseinhibitor pargyline, and the atypical antidepressant bupropion,even though they did not differ in baseline immobility fromDbh^+/– 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 severelyattenuated in the Dbh^–/– mice. In contrast, citalopram(the most selective SSRI) was equally effective at reducingimmobility in mice with and without NE. Restoration of NE byusing L-threo-3,4-dihydroxyphenylserine reinstated the behavioraleffects of both desipramine and paroxetine in Dbh^–/–mice, thus demonstrating that the reduced sensitivity to antidepressantsis related to NE function, as opposed to developmental abnormalitiesresulting from chronic NE deficiency. Microdialysis studiesdemonstrated that the ability of fluoxetine to increase hippocampalserotonin was blocked in Dbh^–/– mice, whereas citalopram'seffect was only partially attenuated. These data show that NEplays an important role in mediating acute behavioral and neurochemicalactions 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.

Present address: Neuroscience Disease Area, Novartis Institutesfor Biomedical Research, Novartis Pharma AG, CH-4002 Basel,Switzerland.

^¶ Present address: Department of Neurobiology and Anatomy, DrexelUniversity 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}pharm.med.upenn.edu.

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Antidepressant Activity Requires Norepinephrine: (1 June 2004)
Sci. STKE 2004 (235), tw193. [DOI: 10.1126/stke.2352004TW193]
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