Abstract
The relationship between the ability of repeated desipramine treatment to cause downregulation of the norepinephrine transporter (NET) and produce antidepressant-like effects on behavior was determined. Treatment of rats with 15 mg/kg per day desipramine reduced NET expression, measured by 3H-nisoxetine binding and SDS–PAGE/immunoblotting, in cerebral cortex and hippocampus and reduced the time of immobility in the forced-swim test. The antidepressant-like effect on forced-swim behavior was evident 2 days following discontinuation of desipramine treatment when plasma and brain levels of desipramine and its major metabolite desmethyldesipramine were not detectable. Reduced NET expression resulted in reduced norepinephrine uptake, measured in vitro, and increased noradrenergic neurotransmission, measured in vivo using microdialysis. Overall, the dose–response and time-of-recovery relationships for altered NET expression matched those for production of antidepressant-like effects on behavior. The importance of increased noradrenergic neurotransmission in the persistent antidepressant-like effect on behavior was confirmed by demonstrating that it was blocked by inhibition of catecholamine synthesis with α-methyl-p-tyrosine. The present results suggest an important role for NET regulation in the long-term behavioral effects of desipramine and are consistent with clinical data suggesting that enhanced noradrenergic neurotransmission is necessary, but not sufficient, for its antidepressant actions. Understanding the mechanisms underlying NET regulation in vivo may suggest novel targets for therapeutic intervention in the treatment of depression.
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Acknowledgements
We thank Drs Bernd Meibohm and Lisa Tang for advice and assistance on the measurement of plasma and brain levels of desipramine and desmethyldesipramine. This work was supported by research grants from the National Institute of Mental Health (MH051175, MH040694, and MH072672).
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JM O’Donnell and H-T Zhang have received research support from Memory Pharmaceuticals and Lundbeck Pharmaceuticals.
Z Zhao, A Baros, M Lapiz, C Bondi, and D Morilak declare no financial interests that could be perceived as constituting a potential conflict of interest.
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Zhao, Z., Baros, A., Zhang, HT. et al. Norepinephrine Transporter Regulation Mediates the Long-Term Behavioral Effects of the Antidepressant Desipramine. Neuropsychopharmacol 33, 3190–3200 (2008). https://doi.org/10.1038/npp.2008.45
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DOI: https://doi.org/10.1038/npp.2008.45
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