INHIBITION BY ANTIDEPRESSANT DRUGS OF CYCLIC-AMP RESPONSE ELEMENT-BINDING PROTEIN CYCLIC AMP RESPONSE ELEMENT-DIRECTED GENE-TRANSCRIPTION/

Clinical observations agree that antidepressant drugs are effective on ly after a lag phase of 1-3 weeks. This delay could be explained at th e molecular level by an action on gene transcription. Transcription of many genes is directed by the cAMP/Ca2+-responsive element (CRE) and its cognate transcription factor CRE-binding protein (CREB). Membrane depolarization and cAMP induce the phosphorylation of CREB at Ser-119 and thereby stimulate the transcriptional activity of CREB. The effect of antidepressant drugs on CREB/CRE-directed gene transcription was i nvestigated using transient transfections of reporter fusion genes in HIT and PC-12 cells. Clomipramine, imipramine, fluoxetine, doxepin, de sipramine, amitriptyline, maprotiline, mianserin, and trazodone inhibi ted CRE-directed gene transcription that was stimulated by membrane de polarization, with IC50 values between 70 nM and 1.73 mu M. Desipramin e had no effect on transcription after stimulation by cAMP but blocked the synergistic effect of cAMP and membrane depolarization to the lev el of stimulation by cAMP alone, Upon membrane depolarization, desipra mine reduced the phosphorylation of CREB at Ser-119 and also blocked t he depolarization-induced increase in the intracellular free Ca2+ conc entration in HIT cells. Thus, by interfering with the depolarization-i nduced activation of the transcription factor CREB, antidepressant dru gs can inhibit CRE-directed gene transcription, which could underlie t he pharmacological effects of these clinically important drugs.