Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism Phenotypes
Annual rept. 8 Aug 2013-7 Aug 2014
NORTH CAROLINA UNIV AT CHAPEL HILL
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Currently, there are no established pharmaceutical strategies that effectively treat core autism spectrum disorder ASD symptoms, including pervasive social deficits and repetitive behaviors. The oxytocin pathway has an important role in normal human social behaviors, and oxytocin dysregulation has been implicated in ASD-associated behavioral symptoms. There is now emerging evidence that oxytocin has therapeutic efficacy in ameliorating core ASD symptoms associated with social behavior. However, from the standpoint of drug discovery, oxytocin is a poor candidate as a standard clinical treatment. Oxytocin is rapidly metabolized and has low brain penetrance with peripheral administration. The goal of the proposed studies is to discover new small-molecule compounds that enhance oxytocin signaling, as novel drug interventions for social deficits and abnormal repetitive behavior relevant to ASD. In this third year, we have extended our published findings that oxytocin can effectively overcome representative ASD phenotypes in two mouse lines that model ASD-like behaviors, including overt alterations in social behavior, and we have confirmed these effects in a genetic model of social impairment, the Grin1 knockdown mouse. We have also evaluated one synthetic oxytocin agonist, Compound 39, and one oxytocin metabolite, for efficacy against social deficits in BALBcByJ mice, and we are currently evaluating a second oxytocin metabolite for prosocial effects. Overall, we have successfully validated three mouse models for as preclinical screens for compounds targeting the oxytocin receptor, and provided leads for a drug discovery campaign for social deficits and other core autism symptoms.
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