A New Vasopressin V1a Antagonist Restores Normal Social Behavior and Reveals a Specific Brain Network in the Rat Valproate Model of Autism

Background:  The neuropeptide vasopressin plays an important role in regulating social behavior. In humans, prenatal exposure to the anticonvulsant drug valproate (VPA) has been associated with an increased risk of autism in the newborn. In rats, a single injection of valproate to pregnant dams at day 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. Based on synaptic and phenotypic similarities, the rat VPA model can be considered a valid model of human autism.

Objectives:  Investigate the role of central vasopressin 1a (V1a) receptor signaling on the phenotype of the rat valproate model of autism.

Methods: From postnatal day 60 on rats prenatally exposed to VPA were treated daily during 3 weeks with a new brain penetrant V1a receptor-specific small molecule antagonist. Their behavior was assessed in the Morris water-maze and in the 3-chamber social interaction test. Long term potentiation was measured in hippocampal slices. Finally, VPA rats and wild-type controls were scanned by functional magnetic resonance imaging at postnatal day 60 and after 1-week 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 V1a receptor-specific small molecule antagonist completely reversed the impairments in social behavior, spatial memory and learning typically seen in VPA rats. In line with the behavioral finding, the hippocampal LTP deficit seen in VPA rats was normalized by the compound. In functional magnetic resonance imaging VPA rats were found to be characterized by reduced brain perfusion in cortex, nucleus accumbens, hippocampus and amygdala and increased brain perfusion in VTA, dorsal striatum and thalamus compared to control rats. Chronic V1a antagonism specifically normalized brain perfusion in amygdala, dorsal striatum and VTA.

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