A New Vasopressin V1a Antagonist Reveals a Brain Network Involved in the Symptomatology of the Rat Valproate Model of Autism

Background: The use of the anticonvulsant drug valproate during pregnancy increases the risk for development of autism in children, accordingly the rat valproate model of autism has neuroanatomical and phenotypical similarities to human autism. A single injection of valproate to pregnant dams at days 12.5 of gestation, the time of the neural tube closure, induces a range of behavioral abnormalities in the offspring, such as deficits in social behavior, working and spatial memory and increased locomotor activity.

Objectives: With oxytocin, vasopressin is a neuropeptide thought to play an important role in regulating social behavior. We therefore wanted to investigate the role played by vasopressin in the phenotype of the rat valproate (VPA) model of autism. 

Methods: Rats prenatally exposed to VPA were treated from postnatal day 60 daily for 3 weeks with a new, brain penetrant, vasopressin V1a receptor-specific small molecule antagonist. Their behavior was assessed in the Morris water-maze and in the 3 chamber social interaction test. Another group of VPA rats and wild-type controls was scanned by functional magnetic resonance imaging at postnatal day 60 and after 3 weeks chronic V1a antagonist treatment, to reveal changes in brain perfusion due to prenatal exposure to VPA and potential normalization by V1a antagonism.

Results: Chronic treatment for 3 weeks with our vasopressin V1a receptor-specific small molecule antagonist, completely reversed the impairments in social behavior, spatial memory and learning typically seen in VPA rats. In functional magnetic resonance imaging VPA rats are characterized by reduced brain perfusion in cortex, inferior colliculus, raphe, hippocampus and hypothalamus and increased brain perfusion in VTA, dorsal striatum and posterior hippocampus compared to control rats. Chronic V1a antagonism specifically normalized brain perfusion in dorsal striatum, VTA and colliculus.

Conclusions: These data show that chronic inhibition of vasopressin V1a receptors rescues normal behavior in VPA rats by normalizing perfusion in a brain network important for salience detection, sensory processing and reward. These results suggest that V1a antagonists have the potential to improve social interaction deficit in autism, a core symptom for which there is currently no drug treatment.