Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine.
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 (3)H-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 alpha-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.
Zhao
Zaorui
Z
Graduate Program in Pharmaceutical and Pharmacological Sciences, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA. zzhao@hsc.wvu.edu
Baros
Alicia M
AM
Zhang
Han-Ting
HT
Lapiz
M Danet S
MD
Bondi
Corina O
CO
Morilak
David A
DA
O'Donnell
James M
JM
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013995:Time; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D005473:Fluoxetine; C011386:nisoxetine; D019805:alpha-Methyltyrosine; D003891:Desipramine; D009638:Norepinephrine