Currently, there are no established pharmaceutical strategies that effectively treat core autism spectrum disorder (ASD) symptoms, including pervasive social deficits and repetitive behaviors. Instead, pharmacological treatment of ASD with atypical antipsychotics or selective serotonin uptake inhibitors, such as fluoxetine, can reduce irritability, impulsivity, and overt motor stereotypy, but are ineffectual in enhancing social motivation. Significant evidence suggests that the neuropeptide hormone oxytocin has an important role in controlling normal human social behaviors, and deficits in the oxytocin pathway have been associated with ASD-associated behavioral symptoms. Remarkably, oxytocin itself has demonstrable effects in ameliorating core ASD symptoms associated with social behavior. However, from the standpoint of drug discovery, oxytocin is a poor drug candidate because of several unsatisfactory properties. Oxytocin only lasts 2-5 minutes in human serum, and oxytocin is a highly charged peptide making crossing the blood-brain barrier a very real challenge. In the proposed studies, we will validate the oxytocin receptor as a small-molecule drug target for treating social deficits and abnormal repetitive behavior relevant to ASD phenotypes. This approach is based on the idea that activating the oxytocin pathway will overcome social deficits, repetitive behavior, and other phenotypes associated with ASD. To conduct this work, we will first establish that oxytocin can effectively overcome representative ASD phenotypes in three mouse lines that model ASD-like behaviors, including overt alterations in social behavior and abnormal repetitive behavior. We will prioritize synthetic compounds that activate the oxytocin receptor using cell-based assays, and we will evaluate the therapeutic efficacy of the top molecules in the characterized mouse lines. The proposed research employs a highly innovative screening paradigm to identify activators of oxytocin function relevant to treatment strategies for ASD. The first major innovation is the use of recently developed mouse models. The second innovation is the type of compounds we will study as potential therapeutic agents to treat ASD symptoms. One type of molecule we will investigate behaves like the endogenous hormone oxytocin by binding to and activating the oxytocin receptor. These are called agonists and represent a traditional approach towards pathway activation. The second class of compound we will study acts by increasing the activity of oxytocin itself at the oxytocin receptor much like an amplifier. This class of compound is called a positive allosteric modulator and is expected to have much greater selectivity in its action, thus decreasing potential side effects. The successful completion of these studies is likely to have a high impact because there are currently no approved drugs for treating the profound behavioral abnormalities found in ASD. The successful completion of the proposed aims will validate the oxytocin receptor as a small-molecule drug target for the amelioration of ASD-associated phenotypes, contribute to the drug discovery process by validating mouse models for preclinical testing, and provide leads for a drug discovery campaign directed at the oxytocin receptor. This project is linked to Department of Defense project AR100231.