Effects of desipramine treatment on norepinephrine transporter gene expression in the cultured SK-N-BE(2)M17 cells and rat brain tissue.
The antidepressant desipramine (DMI) is a selective inhibitor of norepinephrine (NE) transport that down-regulates the norepinephrine transporter (NET) protein in a concentration- and time-dependent manner in vitro. In this study, possible regulatory effects of DMI on NET mRNA and protein levels were investigated with the NET-expressing SK-N-BE(2)M17 cell line and rat brain tissue. Northern blot analysis showed that incubation of the cultured cells with DMI (5-500 nm) for 3 days reduced levels of NET mRNA in both its 5.8-kb (by up to 58%) and 3.6-kb forms (to 68%), whereas incubation for 14 days increased both levels (to 40% and 100%) in a concentration-dependent manner. In contrast, NET protein levels decreased after 3-14 days of exposure of the cells to DMI, as determined by western blotting. The in vitro findings were supported by in vivo treatment of rats with DMI. Thus, in situ hybridization demonstrated initially decreased, and later increased, NET mRNA levels in locus coeruleus (LC) tissue of rats treated with DMI; whereas NET protein levels in the LC were reduced after 14 days, but unchanged after three daily DMI treatments. Thus, DMI had similar effects on NET expression in vitro and in vivo, with opposite changes in NET mRNA and protein levels, suggesting that the regulatory mechanisms involved are complex and non-congruent.
Zhu
Meng-Yang
MY
Molecular Neurobiology Laboratory, Mailman Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Kim
Chun-Hyung
CH
Hwang
Dong-Youn
DY
Baldessarini
Ross J
RJ
Kim
Kwang-Soo
KS
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493227:SLC6A2 protein, human; C493226:Slc6a2 protein, rat; D027981:Symporters; D003891:Desipramine