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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3190-3200 |
| Number of pages | 11 |
| Journal | Neuropsychopharmacology |
| Volume | 33 |
| Issue number | 13 |
| DOIs | |
| State | Published - Dec 2008 |
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Keywords
- α-methyl-p- tyrosine
- Antidepressant drugs
- Depression
- Desipramine
- Norepinephrine
- Norepinephrine transporter
ASJC Scopus subject areas
- Pharmacology
- Psychiatry and Mental health
Cite this
Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine. / Zhao, Zaorui; Baros, Alicia M.; Zhang, Han Ting; Lapiz, M. Danet S; Bondi, Corina O.; Morilak, David A; O'Donnell, James M.
In: Neuropsychopharmacology, Vol. 33, No. 13, 12.2008, p. 3190-3200.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine
AU - Zhao, Zaorui
AU - Baros, Alicia M.
AU - Zhang, Han Ting
AU - Lapiz, M. Danet S
AU - Bondi, Corina O.
AU - Morilak, David A
AU - O'Donnell, James M.
PY - 2008/12
Y1 - 2008/12
N2 - 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.
AB - 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.
KW - α-methyl-p- tyrosine
KW - Antidepressant drugs
KW - Depression
KW - Desipramine
KW - Norepinephrine
KW - Norepinephrine transporter
UR - http://www.scopus.com/inward/record.url?scp=57349112330&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=57349112330&partnerID=8YFLogxK
U2 - 10.1038/npp.2008.45
DO - 10.1038/npp.2008.45
M3 - Article
C2 - 18418364
AN - SCOPUS:57349112330
VL - 33
SP - 3190
EP - 3200
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 13
ER -