Increased glucocorticoid receptor gene promoter activity after antidepressant treatment.
We have tested the hypothesis that antidepressants affect the expression of the glucocorticoid receptor gene, by looking at glucocorticoid receptor gene promoter activity, glucocorticoid receptor mRNA levels, and glucocorticoid-binding activity after treatment of different cell lines with desipramine. Treatment of LTK- cells or Neuro 2A cells with desipramine produced a 50-200% increase in chloramphenicol acetyltransferase activity transcribed from a 2.7-kilobase glucocorticoid receptor gene promoter region. In cell lines derived from both neuronal and non-neuronal sources, glucocorticoid receptor mRNA concentration doubled after desipramine treatment, and this was associated with a 2-fold higher functional glucocorticoid binding capacity and increased glucocorticoid sensitivity, as measured with the reporter plasmid pMMTVCAT. Antidepressant-induced increases in glucocorticoid receptor gene promoter activity, glucocorticoid receptor mRNA levels, and functional glucocorticoid binding activity suggest a novel mechanism of action for these drugs on the hypothalamic-pituitary-adrenal axis.
Pepin
M C
MC
Molecular Psychogenetics Laboratory, Research Center, Ste Foy, Québec, Canada.
Govindan
M V
MV
Barden
N
N
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D002678:Chimera / Q000235:genetics; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D003891:Desipramine / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012680:Sensitivity and Specificity; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D000928:Antidepressive Agents; D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015500:Chloramphenicol O-Acetyltransferase; D003891:Desipramine