PROJECT SUMMARY The goal of this study is to investigate the role of the kappa opioid receptor (KOR) in the symptomatology of borderline personality disorder (BPD), a condition associated with alarmingly elevated risk for suicide attempt (up to 75%) and death by suicide (up to 10%). Despite BPD’s relatively low prevalence (1-5%), an epidemiological study reported that more than two thirds of recent suicide attempts occurred in individuals with BPD. Unfortunately, most of the available treatments are not capable of addressing overall BPD symptom severity or rapidly reducing suicide risk. Magnetic resonance imaging studies have identified structural and network alterations in BPD symptom presentation and have associated fronto-limbic circuit dysregulation with an increase in BPD symptom severity. Investigation of molecular mechanisms responsible for BPD symptoms, and suicide risk specifically is an essential next step to both promote development of novel treatments and facilitate risk prevention in BPD. Emerging evidence implicates KOR in BPD and suicidal behavior. KOR plays critical roles in emotion regulation, social functioning, and pain perception – all of which are both central to BPD and related to suicide risk. Postmortem studies have shown an association between KOR and death by suicide. Further, a variety of studies in both animals and humans have shown that KOR targeted medications can produce antidepressant, anxiolytic, and even anti-suicidal effects. Importantly, KOR agents’ effect on dopamine is modest relative to drugs of abuse, reducing concerns about abuse potential. Here, we propose a novel investigation of KOR availability of in individuals with BPD using positron emission tomography (PET), a brain imaging technique, and radioligand [11C]EKAP which binds selectively to KOR in the brain (Aim 1). Given the high prevalence of suicide-related behavior in BPD, we will also evaluate the association between KOR availability, suicide attempt history, and current suicidal thoughts in BPD (Aim 2). Lastly, we will evaluate the association between impulsivity, pain tolerance, and self-injury – key endophenotypes of BPD and which are resistant to treatment – and KOR availability (Aim 3). Results of this study will provide potentially critical insight into the relationship between this novel molecular target, BPD symptom presentation, and suicidal behavior. Based on findings we will pursue funding for a larger PET study to test potential non-addictive KOR targeted medications for both overall BPD symptom reduction, and suicide risk.