title: Mood stabilizers inhibit glucocorticoid receptor function in LMCAT cells.
abstract: Mood stabilizers block some central effects induced by stress and glucocorticosteroids; however, little is known about interaction of these drugs with glucocorticoid receptor function. In the present study, we evaluated effects of lithium, valproate and carbamazepine on glucocorticoid receptor-mediated gene expression in mouse fibroblast cells (L929), stably transfected with mouse mammary tumor virus (MMTV)-chloramphenicol acetyltransferase reporter plasmid (LMCAT cells). Treatment of LMCAT cells with lithium (1-4 mM), valproate (0.1-3 mM) and carbamazepine (30 and 100 microM) inhibited corticosterone-induced activity of reporter gene in a time- and concentration-dependent manner. Furthermore, it was found that valproate, but not two other antimanic drugs, decreased the glucocorticoid receptor level in cytosolic and nuclear fraction, and its inhibitory effect on glucocorticoid receptor-mediated transcriptional activity was attenuated by c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) inhibitor. Protein kinase B (PKB), glycogen synthase kinase (GSK), p38-MAPK and depletion of inositol were not shown to be involved in the mechanism of mood-stabilizer action on glucocorticoid receptor function under present experimental condition. In contrast to mood stabilizers, amphetamine (1-100 microM) had no effect on glucocorticoid receptor-mediated transcriptional activity. These findings corroborate the hypothesis that direct effects of antidepressants and mood stabilizers on glucocorticoid receptor function is an important mechanism, by which these drugs may inhibit some deleterious effects of stress and glucocorticoids on the central nervous system.
authors.affiliation: Department of Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Basta-Kaim
authors.forename: Bogusława
authors.initials: B
authors.lastname: Budziszewska
authors.forename: Lucylla
authors.initials: L
authors.lastname: Jaworska-Feil
authors.forename: Magdalena
authors.initials: M
authors.lastname: Tetich
authors.forename: Marta
authors.initials: M
authors.lastname: Kubera
authors.forename: Monika
authors.initials: M
authors.lastname: Leśkiewicz
authors.forename: Władysław
authors.initials: W
authors.lastname: Lasoń
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002220:Carbamazepine / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D003345:Corticosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007294:Inositol / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051571:Protein Kinase C-alpha; D011725:Pyridines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000873:Anthracenes; D018692:Antimanic Agents; D005419:Flavonoids; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D011725:Pyridines; D011965:Receptors, Glucocorticoid; C417521:SB 216763; D013629:Tamoxifen; C432165:pyrazolanthrone; D002220:Carbamazepine; D007294:Inositol; D014635:Valproic Acid; D008094:Lithium; D000661:Amphetamine; D015500:Chloramphenicol O-Acetyltransferase; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D003345:Corticosterone