Effects of selective sigma receptor ligands on glucocorticoid receptor-mediated gene transcription in LMCAT cells.
It has been shown previously that sigma receptor agonists reveal potential antidepressant activity in experimental models. Moreover, some data indicate sigma receptor contribution to stress-induced responses (e.g., conditioned fear stress in mice), though the mechanism by which sigma ligands can exert their effects, remains unclear. Recent studies have indicated that antidepressant drugs (ADs) inhibit glucocorticoid receptor (GR) function in vitro. The aim of the present study was to find out whether sigma receptor ligands are able to directly affect GR action. To this end, we evaluated the effect of sigma receptor agonists and antagonists on GR function in mouse fibroblast cells (L929) stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) plasmid (LMCAT cells). For this study, we chose SA4503, PRE 084, DTG (selective sigma(1) or sigma(1/2) receptor agonists) and BD 1047, SM 21, rimcazole (sigma receptor antagonists). Fluvoxamine, the selective serotonin reuptake inhibitor with sigma(1/2) receptor affinity, was used for comparison. It was found that SM 21 (at 1, 3, 10 and 30 microM), BD 1047 (3, 10 and 30 microM) rimcazole (10 microM), and fluvoxamine (at 3, 10 and 30 microM) significantly inhibited corticosterone-induced gene transcription, while DTG, SA 4503 and PRE 084 remained ineffective. Thus, the sigma receptor agonists that predominantly showed antidepressant-like activity in behavioral models, were without effect in this in vitro model. These results suggest that antidepressant-like activity of sigma receptor agonists is independent of corticosterone-induced gene transcription. Therefore, the attenuation of GR function induced by sigma receptor antagonists remains ambiguous and requires further study.
Skuza
Grazyna
G
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland. skuza@if-pan.krakow.pl
Rogóz
Zofia
Z
Szymańska
Magdalena
M
Budziszewska
Bogusława
B
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D003345:Corticosterone / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D017480:Receptors, sigma / Q000819:agonists / Q000502:physiology*; D014158:Transcription, Genetic
D000928:Antidepressive Agents; D005029:Ethylenediamines; D008024:Ligands; D010879:Piperazines; D011965:Receptors, Glucocorticoid; D017480:Receptors, sigma; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C101789:SA 4503; D015500:Chloramphenicol O-Acetyltransferase; D003345:Corticosterone