A Role for CREB in Antidepressant Action

Abstract

A role for monoamine neurotransmitter systems, particularly norepinephrine (NE) and serotonin (5-HT), in the actions of antidepressant treatments is supported by preclinical and clinical studies (1–4). Many antidepressant treatments block the reuptake or metabolism of NE and 5-HT and acutely increase synaptic levels of these monoamines. However, the therapeutic action of antidepressants is dependent on chronic treatment, leading to the hypothesis that adaptations to the acute elevation of NE and 5-HT underlie the therapeutic effects of antidepressants. Early studies focused on adaptations of NE and 5-HT receptors and the second messenger systems regulated by these receptors (5,6). Advances in molecular and cellular neurobiology have demonstrated that the receptor-coupled second messenger systems represent the first step in a cascade of intracellular messengers and regulatory proteins. These intracellular cascades control virtually every aspect of neuronal function, including the regulation of gene transcription. It is reasonable to hypothesize that adaptations of these intracellular sites are responsible for the therapeutic action of antidepressant treatments (7–11).