Our understanding of the pathophysiology underlying major depressive disorder (MDD) is incomplete. A great deal of research has focused on the role of disruptions in monoamine neurotransmitter systems in the etiology of MDD (Leonard 2000), and all existing classes of FDA-approved antidepressant medication act on these systems (Lopez-Munoz and Alamo 2009). However, only a minority of patients with MDD achieve remission after well-administered therapeutic trials of existing antidepressant medications (Trivedi et al 2006). Novel studies investigating other molecular pathways that may be involved in the pathophysiology of MDD are needed, and may in turn suggest opportunities for the development of new antidepressant treatments. Both early life and recent life stress are potent risk factors for the development of MDD in adulthood. The kappa opioid receptor (KOR) is stimulated by the endogenous kappa opioids, dynorphins, in response to stress. Evidence from a large, consistent animal literature, and from several studies in humans, suggests that KOR stimulation may contribute to the pathophysiology of MDD, and that KOR may therefore represent a novel molecular target for the development of antidepressant medications. KOR is stimulated by dynorphins in response to stress;KOR agonists exacerbate several animal models of depression, and KOR antagonists have antidepressant effects in these models. In humans, KOR agonists lead to dysphoria in normal controls, and have therapeutically mood-lowering (anti-manic) properties in one study in bipolar disorder. KOR stimulation may exert effects on mood through modulating dopamine release in the nucleus accumbens, a brain region central to processing reward which is implicated in the pathophysiology of depression, and through modulatory effects on serotonin release. The primary aim of this study is to compare regional brain KOR binding potential (BPF, proportional to the total number of available receptors) between subjects with MDD and healthy controls in vivo using positron emission tomography (PET), which has not been assessed to date. This will be done using a KOR-specific PET tracer validated in our institution and characterized further in a human test-retest reliability study, [11C]GR103545. Lower KOR BPF in subjects with MDD compared to controls is hypothesized in two regions implicated in the pathophysiology of MDD in which KOR activation occurs in response to stress: ventral striatum and hippocampus. This hypothesis is based on activation of KOR in animal models of depression, which leads to compensatory KOR downregulation. In an exploratory manner, the relationship between life stress and KOR binding will be examined, to translate this finding from rodents into humans. Both early life abuse/neglect and recent stressful life events will be examined as predictors of KOR binding. This study may identify a biological pathway through which environmental adversity contributes to the development of MDD, and may provide a rationale for further development of a novel class of antidepressant, the KOR antagonists. PUBLIC HEALTH RELEVANCE: Approximately 33 million adults in the United States (15% of the U.S. population) have suffered from major depressive disorder during their lifetime, and approximately 13 million Americans have experienced MDD in the past year (Kessler et al 2003). Existing treatments for depression are effective in only a minority of patients. Increasing our understanding of the role of the kappa opioid system in the pathophysiology of depression would provide the rationale for further development of a new class of antidepressant medication that could potentially reduce the very large morbidity and mortality caused by MDD.