Abstract
Regulation of gene transcription via the cAMP-mediated second messenger pathway has been implicated in the actions of antidepressant drugs, but studies to date have not demonstrated such an effect in vivo. To directly study the regulation of cAMP response element (CRE)-mediated gene transcription by antidepressants, transgenic mice with a CRE-LacZ reporter gene construct were administered one of three different classes of antidepressants: a norepinephrine selective reuptake inhibitor (desipramine), a serotonin selective reuptake inhibitor (fluoxetine), or a monoamine oxidase inhibitor (tranylcypromine). Chronic, but not acute, administration of these antidepressants significantly increased CRE-mediated gene transcription, as well as the phosphorylation of CRE binding protein (CREB), in several limbic brain regions thought to mediate the action of antidepressants, including the cerebral cortex, hippocampus, amygdala, and hypothalamus. These results demonstrate that chronic antidepressant treatment induces CRE-mediated gene expression in a neuroanatomically differentiated pattern and further elucidate the molecular mechanisms underlying the actions of these widely used therapeutic agents.