The biochemical underpinnings of complex social behavior are poorly understood. As a result of this knowledge gap, diseases and syndromes that result in social deficits cannot be effectively treated and rational approaches toward establishing effective treatment are restricted. Recently, the neuropetide oxytocin, which has well established roles in parturition and lactation, has been implemented in a wide range of complex social behaviors. Results from several reports suggest that oxytocin can positively affect anxiety, depression, psychosis and addiction. Additionally, the potency of oxytocin in forming social attachments (mother-infant, monogamous pair bonds) and social memories suggests that increased oxytocin activity in the brain can ameliorate the profound social motivation and cognition deficits of patients with autism spectrum disorders, schizophrenia or severe personality disorders. Social deficits are particularly disabling features of these disorders for which we have no effective pharmacological treatments. The hypothesis of this research project is that oxytocin receptor agonist and positive allosteric modulators would serve as leads for pharmaceutical intervention in disease states characterized by social deficits. Our objective is to identify agonists and positive allosteric modulators through a high throughput screen. To achieve our object we propose three specific aims: 1. Identify selective allosteric potentiators and agonists of the human OTR through a high throughput screening campaign. 2. Conduct post screen secondary analysis to validate hits identified in our high throughput screen. In order to validate hits from the primary screen, several cell-based secondary assays will be conducted. We have developed each assay for this purpose. 3. Develop a plan for optimization of validated hits. We will develop a plan to optimize the more promising class of actives identified through our screening efforts. The completion of these aims will provide the scientific community with new chemical probes to study the roles of oxytocin in complex mammalian social behavior. PUBLIC HEALTH RELEVANCE: Oxytocin is a peptide hormone that affects complex social behaviors in mammals. Deficits in the oxytocin pathway have been implemented in several human diseases and disorders, including schizophrenia and Autism, but there remains a severe dearth of chemical probes to interrogate the oxytocin pathway and to develop pharmaceutical agents. This proposal describes a high throughput screen to identify oxytocin receptor agonists and positive allosteric modulators to be used as leads for the design of chemical probes to investigate the oxytocin pathway with particular attention to its role in social behavior.