cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment

Regulation of gene transcription via the cAMP-mediated second messenger pat hway has been implicated in the actions of antidepressant drugs, but studie s to date have not demonstrated such an effect in vivo. To directly study t he regulation of cAMP response element (CRE)-mediated gene transcription by antidepressants, transgenic mice with a CRE-LacZ reporter gene construct w ere administered one of three different classes of antidepressants: a norep inephrine selective reuptake inhibitor (desipramine), a serotonin selective reuptake inhibitor (fluoxetine), or a monoamine oxidase inhibitor (tranylc ypromine). Chronic, but not acute, administration of these antidepressants significantly increased CRE-mediated gene transcription, as well as the pho sphorylation of CRE binding protein (CREB), in several limbic brain regions thought to mediate the action of antidepressants, including the cerebral c ortex, hippocampus, amygdala, and hypothalamus. These results demonstrate t hat chronic antidepressant treatment induces CRE-mediated gene expression i n a neuroanatomically differentiated pattern and further elucidate the mole cular mechanisms underlying the actions of these widely used therapeutic ag ents.