Role of Estradiol in the Expression of Genes Involved in Serotonin Neurotransmission: Implications for Female Depression

BACKGROUND: In women, changes in estrogen levels may increase the incidence and/or symptomatology of de-pression and affect the response to antidepressant treatments. Estrogen therapy in females may provide some mood benefits as a single treatment or might augment clinical response to antidepressants that inhibit serotonin reuptake. OBJECTIVE: We analyzed the mechanisms of estradiol action involved in the regulation of gene expression that modulates sero-tonin neurotransmission implicated in depression. METHOD: Publications were identified by a literature search on PubMed. RESULTS: The participation of estradiol in depression may include regulation of the expression of tryptophan hydroxylase-2, monoamine oxidase A and B, serotonin transporter and serotonin-1A receptor. This effect is mediated by estradiol binding to intracellular estrogen receptor that interacts with estrogen response elements in the promoter sequences of tryptophan hy-droxylase-2, serotonin transporter and monoamine oxidase-B. In addition to directly binding deoxyribonucleic acid, estrogen receptor can tether to other transcription factors, including activator protein 1, specificity protein 1, CCAAT/enhancer bind-ing protein β and nuclear factor kappa B to regulate gene promoters that lack estrogen response elements, such as monoamine oxidase-A and serotonin 1A receptor. CONCLUSION: Estradiol increases tryptophan hydroxylase-2 and serotonin transporter expression and decreases the expres-sion of serotonin 1A receptor and monoamine oxidase A and B through the interaction with its intracellular receptors. The understanding of molecular mechanisms of estradiol regulation on the protein expression that modulates serotonin neuro-transmission will be helpful for the development of new and more effective treatment for women with depression.