clozapine and adenosine-3--5--cyclic-phosphorothioate

Antipsychotic drugs can modulate transcription factors and also nuclear receptors, but their action on glucocorticoid receptors (GR)-members of the steroid/thyroid hormone receptor family has not been studied so far. In the present study we investigated effects of various antipsychotics on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with a mouse mammary tumor virus promoter (LMCAT cells). Chlorpromazine (3-100 microM) inhibited the corticosterone-induced gene transcription in a concentration- and time-dependent manner. Clozapine showed a similar, but less potent effect, while haloperidol acted only in high concentrations, and other antipsychotic drugs (sulpiride, raclopride, remoxipride) were without any effect. It was also found that a phorbol ester (an activator of protein kinase C (PKC)) and A-23187 (Ca(2+)-ionophore) attenuated the inhibitory effect of chlorpromazine on the GR-induced gene transcription. An antagonist of the L-type Ca(2+) channel, as well as an inhibitor of phospholipase C (PLC) inhibited the corticosterone-induced gene transcription, but had no effect on the chlorpromazine-induced changes. The involvement of a PKC/PLC pathway in the chlorpromazine action was confirmed by Western blot analysis which showed that the drug in question decreased the PLC-beta(1) protein level, and to a lesser extent that of the PKC-alpha protein in LMCAT cells. The aforementioned data suggest that inhibition of the glucocorticosteroid-induced gene transcription by chlorpromazine and clozapine may be a mechanism by which these drugs block some effects induced by glucocorticoids. The inhibitory effect of chlorpromazine on the corticosterone-induced gene transcription seems to depend on the inhibition of Ca(2+) influx and/or the inhibition of some calcium-dependent enzymes, e.g. phospholipase beta(1).

Topics: Animals; Antipsychotic Agents; Calcimycin; Calcium; Calcium Channel Blockers; Cell Line; Cell Line, Transformed; Chloramphenicol O-Acetyltransferase; Chlorpromazine; Clozapine; Colforsin; Cyclic AMP; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Estrenes; Fibroblasts; Gene Expression Regulation; Genes, Reporter; Haloperidol; Histamine; Histamine H1 Antagonists; Ionophores; Mammary Tumor Virus, Mouse; Mice; Nifedipine; Phorbol Esters; Phosphodiesterase Inhibitors; Protein Kinase C; Protein Kinase C-alpha; Pyrilamine; Pyrrolidinones; Raclopride; Receptors, Glucocorticoid; Remoxipride; Sulfonamides; Sulpiride; Tetradecanoylphorbol Acetate; Thionucleotides; Transcription, Genetic; Type C Phospholipases