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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 -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.
¶ 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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,
Olivia F. O'Leary 
, 
,
Sung-Ha Jin 
-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 
Present address: Neuroscience Disease Area, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. 
