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Mouse Models of Autism Phenotypes As Preclinical Screening Platforms for Novel Oxytocinergic Compounds

Thursday, 2 May 2013: 09:00-13:00
Banquet Hall (Kursaal Centre)
B. L. Teng1,2, R. J. Nonneman1,3, V. D. Nikolova1,4, K. L. Agster1,4, T. T. Davis1,2, N. V. Riddick1,4, L. K. Baker1, C. A. Pedersen1,4, M. B. Jarstfer1,2 and S. S. Moy1,4, (1)Carolina Institute for Developmental Disabilities, University of North Carolina School of Medicine, Chapel Hill, NC, (2)UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, (3)Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, (4)Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC
Background: There is emerging evidence that oxytocin (OT) treatment can improve social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, administration of the neuropeptide, which has a short plasma half-life and poor ability to penetrate the blood-brain barrier, is a problematic issue for clinical use. We have recently initiated a drug development program to identify novel, highly selective, non-peptide OT receptor (OTR) agonists. These efforts would be accelerated by animal models to screen drug candidates for efficacy against ASD-relevant phenotypes.

Objectives: Validate mouse models for preclinical screening of compounds that target the OT pathway, in order to facilitate the development of therapeutics for core ASD symptoms.

Methods: BALB/cByJ and C58/J are well-characterized inbred mouse strains that exhibit behavioral phenotypes relevant to ASD. To validate these models as preclinical screens, mice were tested for OT effects on sociability in a three-chamber task and perseverative responses in a marble-burying assay. C58/J was also examined for OT effects on repetitive behavior and open field activity. These screening platforms were then used to evaluate Compound 39 (a synthetic, non-peptide OTR agonist).

Results: The acute OT regimen did not increase sociability in BALB/cByJ. However, the sub-chronic OT regimen (i.e. four intraperitoneal injections across 7-8 days) had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 hr following the final OT dose in BALB/cByJ, while prosocial effects of OT emerged 1-2 weeks post-treatment in C58/J. An acute OT regimen decreased motor stereotypy in C58/J, at a dose that did not produce sedative or anxiolytic-like effects in open field testing. Similarly, acute OT treatment led to significant reductions in marble-burying by BALB/cByJ. Consistent with previous research, Compound 39 produced some OT-like effects; however, the drug had no effect on sociability.

Conclusions: These studies show that OT reverses social deficits in mouse models of ASD, dependent on dose regimen and genotype. Furthermore, acute OT decreases abnormal repetitive behavior in C58/J and marble-burying in BALB/cByJ. These findings provide validation of the BALB/cByJ and C58/J models as valuable platforms for screening novel drugs for intervention in ASDs, and for elucidating the mechanisms contributing to prosocial and other beneficial effects of OT.

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