M. Otczyk1, K. Mulik1, B. Budziszewska1, L. Jaworska-feil1, A. Basta-kaim1, M. Kubera1, G. Jag£a2,3, W. Nowak2, W. Lasoñ1 Effect of Some Antidepressants on the Low Corticosterone Concentration-induced Gene Transcription in Lmcat Fibroblast Cells

The aim of the present study was to investigate effects of some classical and new antidepressants on functional activity of the glucocorticoid receceptor (GR) induced by low corticosterone concentration in mouse fibroblast cells stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase plasmid (LMCAT cells). We found that the transcriptional activity of GR stimulated by 50 nM corticosterone was strongly attenuated by imipramine, desipramine, fluoxetine and tianeptine in a concentration-dependent way, whereas reboxetine had only a weak effect and venlafaxine was inactive. Further study revealed that the inhibitor of c-Jun N-terminal kinase mitogen-activated protein kinase (JNK-MAPK), SP600125 (0.1 μM), reversed the imipramine-induced suppression of GR function, whereas the inhibitor of extracellular signal-regulated kinase (ERK)-MAPK, PD 98059 (15μM), potentiated the antidepressant action. No effect of selective inhibitors of p38-MAPK, phosphatidylinositol 3-kinase (PI3-K)/Akt, and glycogen synthase kinase (GSK-3) on the imipramine-induced inhibition of GR function was detected. These data indicate that the functional activity of GR evoked by low corticosterone concentration in LMCAT cells is efficiently inhibited by tricyclic antidepressants. Moreover, it was found that JNKand ERK-MAPK were oppositely involved in the regulation of the imipramine-induced inhibition of the GR functional activity. Thus, the present study supports the notion that the interaction of antidepressants with GR may play a role in attenuating pathological hyperactivity of HPA axis in depression.