Pharmacologic Rescue of Impaired Cognitive Flexibility, Social Deficits, Increased Aggression, and Seizure Susceptibility in Oxytocin Receptor Null Mice: A Neurobehavioral Model of Autism

Published:February 09, 2011DOI:


      Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt−/−) and the OT receptor null mice (Oxtr−/−) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization.


      Oxtr−/− mice were characterized for general health, sociability, social novelty, cognitive flexibility, aggression, and seizure susceptibility. Because vasopressin (AVP) and OT cooperate in controlling social behavior, learning, and aggression, they were tested for possible rescue of the impaired behaviors. Primary hyppocampal cultures from Oxtr+/+ and Oxtr−/− mouse embryos were established to investigate the balance between gamma-aminobutyric acid (GABA) and glutamate synapses and the expression levels of OT and AVP (V1a) receptors were determined by autoradiography.


      Oxtr−/− mice display two additional, highly relevant, phenotypic characteristics: 1) a resistance to change in a learned pattern of behavior, comparable to restricted interests and repetitive behavior in autism, and 2) an increased susceptibility to seizures, a frequent and clinically relevant symptom of autism. We also show that intracerebral administration of both OT and AVP lowers aggression and fully reverts social and learning defects by acting on V1a receptors and that seizure susceptibility is antagonized by peripherally administered OT. Finally, we detect a decreased ratio of GABA–ergic versus total presynapses in hippocampal neurons of Oxtr−/− mice.


      Autistic-like symptoms are rescued on administration of AVP and OT to young Oxtr−/− adult animals. The Oxtr−/− mouse is thus instrumental to investigate the neurochemical and synaptic abnormalities underlying autistic-like disturbances and to test new strategies of pharmacologic intervention.

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      • A Complicated Picture of Oxytocin Action in the Central Nervous System Revealed
        Biological PsychiatryVol. 69Issue 9
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          It has been difficult not to notice the massive growth of public awareness and research funding that has steadily increased around autism spectrum disorders (ASD) over the past 10 years. With recent epidemiology studies revealing dramatic rises in prevalence rates that now rival other psychiatric disorders such as schizophrenia, the impact on public health systems and realization of unmet medical needs in ASD has created a growing expectation for improved diagnosis and treatments. Historically considered a backwater of psychiatric drug development, ASD has now captured interest from the pharmaceutical industry (1), which sees significant opportunity in the tractability of a rapidly emerging science around ASD.
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