Abstract
Norepinephrine (NE) is thought to play an important role in the pathophysiology of depression, and in the mechanism of action of antidepressant compounds. Previously, we created mice that are unable to synthesize NE and epinephrine due to targeted disruption of the dopamine-β-hydroxylase gene (Dbh). To specifically test the role of NE in mediating behavioral changes elicited by antidepressants, these mice were examined in the forced swim test. There was no difference in baseline immobility scores in the forced swim test between Dbh+/−mice, which have normal levels of NE, andDbh−/− mice. However, theDbh−/− mice failed to demonstrate antidepressant-like behavioral effects following the administration of several classes of antidepressants. These included the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion. In addition, desipramine significantly reduced immobility in theDbh−/− mice following pretreatment with the synthetic NE precursorl-threo-3,4-dihydroxyphenylserine, but not saline. Biochemical studies showed that there was no significant difference in the regional brain levels of NE transporter immunoreactivity or monoamine oxidase activity, the primary targets for most of the compounds examined. Taken together, these data show that the use of mice that lack endogenous NE may be an important strategy for unraveling the role of NE in tests sensitive to the effects of various psychotherapeutic agents.
Footnotes
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↵1 Current address: Department of Neuropharmacology, The Scripps Research Institute, CVN-7, 10550 N. Torrey Pines Rd., La Jolla, CA 92037.
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↵2 Current address: Department of Psychopharmacology, H. Lundbek, Ottilavej 9, DK-2500 Valby, Denmark.
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This study was supported by a Young Investigator Award to S.T. from the National Alliance for Research on Schizophrenia and Affective Disorders; R01NS37722 to S.T. from National Institute of Neurological Disorders and Stroke; and R01 MH36262 and P05 MH48125 to I.L. from the National Institute of Mental Health.
- Abbreviations:
- NE
- norepinephrine
- AMPT
- α-methyl-p-tyrosine
- Dbh
- dopamine β-hydroxylase
- DSP-4
- N-(2-chloroethyl)-N-2-bromobenzylamine
- FST
- forced swim test
- DOPS
- l-threo-3,4-dihydroxyphenylserine
- MAO
- monoamine oxidase
- NET
- norepinephrine transporter
- ANOVA
- analysis of variance
- TPBS
- Triton phosphate-buffered saline
- Received January 8, 2001.
- Accepted May 2, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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