Postpartum mood disorders affect at least 580,000 American women annually, impede healthy infant and child development, and disrupt families. Despite availability of effective antidepressant medications for postpartum mood disorders, such treatments are often rejected due to fears of medication transfer to a nursing infant and minimization of mental illness in the context of hormonal shifts of childbearing. Identification of a neurobiological marker of postpartum mood disorders has the potential to guide development of more tailored and acceptable treatments for postpartum women. In this application, we propose a serotonergic model of postpartum depression in which maladaptation of limbic serotonin-1 A [5HT1A) receptors to childbearing steroid and peptide hormones comprise an important pathway for postpartum depression onset. The 5HT1A receptor is a well-established molecular target for the action of serotonin, is reduced in depression, and also altered by the childbearing hormones estradiol, progesterone, cortisol and oxytocin. Evaluation of 5HT1A receptor binding in postpartum unipolar disorder (the most common postpartum mood disorder) and during lactation may guide the development of behavioral and hormonal treatments for this disabling and prevalent disorder. Our investigative team has expertise in the clinical disorder, in assessment of reproductive hormones, and in the acquisition and analysis of positron emission tomography 5HT1A receptor data. Additionally, we have preliminary evidence of a 20% reduction in 5HT1A receptor binding in postpartum bipolar depression and a 10% increase in 5HT1A receptor binding in breastfeeding women. We are requesting 2 years of funding to evaluate 5HT1A receptor binding in unipolar postpartum women and to hone in on lactation effects on this receptor system. We will examine 5HT1A receptor binding in the early puerperium (4-8 weeks) in a 2 X 2 design of postpartum women with and without unipolar depressive episodes and who are exclusive breastfeeders or exclusive bottle feeders. Study participation consists of thorough screening and evaluation of subjects for eligibility criteria, a [C-11]WAY- 100635 positron emission tomography scan, a structural magnetic resonance image (for identification of regions of interest on the functional image), and hormonal assessment. Results of this study will inform future studies of novel hormonal and behavioral treatments for postpartum depression. [unreadable] [unreadable] [unreadable]