Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine

Zaorui Zhao, Alicia M. Baros, Han Ting Zhang, M. Danet S Lapiz, Corina O. Bondi, David A Morilak, James M. O'Donnell

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)3190-3200
Number of pages11
JournalNeuropsychopharmacology
Volume33
Issue number13
DOIs
StatePublished - Dec 2008

Fingerprint

Norepinephrine Plasma Membrane Transport Proteins
Desipramine
Antidepressive Agents
Synaptic Transmission
nisoxetine
Therapeutics
Aptitude
Microdialysis
Immunoblotting
Cerebral Cortex
Reaction Time
Catecholamines
Tyrosine
Polyacrylamide Gel Electrophoresis
Hippocampus
Norepinephrine
Down-Regulation
Depression
Brain

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 journalArticle

Zhao, Zaorui ; Baros, Alicia M. ; Zhang, Han Ting ; Lapiz, M. Danet S ; Bondi, Corina O. ; Morilak, David A ; O'Donnell, James M. / Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine. In: Neuropsychopharmacology. 2008 ; Vol. 33, No. 13. pp. 3190-3200.
@article{da7bbc78d47c4ea79c9aebe81a91243d,
title = "Norepinephrine transporter regulation mediates the long-term behavioral effects of the antidepressant desipramine",
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.",
keywords = "α-methyl-p- tyrosine, Antidepressant drugs, Depression, Desipramine, Norepinephrine, Norepinephrine transporter",
author = "Zaorui Zhao and Baros, {Alicia M.} and Zhang, {Han Ting} and Lapiz, {M. Danet S} and Bondi, {Corina O.} and Morilak, {David A} and O'Donnell, {James M.}",
year = "2008",
month = "12",
doi = "10.1038/npp.2008.45",
language = "English (US)",
volume = "33",
pages = "3190--3200",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "13",

}

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 -