A day in the life of a schizophrenic BRAT rat: Pharmacological perturbations of the vasopressin system

Social deficits are present in several neuropsychiatric disorders including schizophrenia, autism spectrum disorders, and anxiety. Moreover, social deficits are one of the prodromal symptoms of schizophrenia that greatly affect quality of life throughout the duration of the disease. The vasopressin (VP) system plays a critical role in social function and impairing VP signaling causes anxiety, social deficits, and social memory deficits. These behavioral deficits are all phenotypes expressed in VP deficient Brattleboro (BRAT) rats and mimic those seen in other animal models of schizophrenia. However, the mechanism by which vasopressin produces these behavioral abnormalities is unclear. Notably, elevations in dopamine signaling as well as reductions in glutamatergic signaling have been associated with behavioral impairments consistent with schizophrenia. In addition to behavioral abnormalities, Event Related Potential (ERP) peaks are reduced in schizophrenia patients and are commonly viewed as an endophenotype of the disease. Consequently, the following studies were performed to 1) determine the specific EEG profile in BRAT rats to assess their face and construct validity as a model for schizophrenia, and 2) to evaluate the pharmacological response properties to agents that alter dopamine or glutamate transmission to assess the potential mechanism by with alterations in VP interact with key neurotransmitter systems of schizophrenia. This study used the BRAT rat to assess the role of vasopressin deficiency in vocal communication during early development and on auditory ERPs during adulthood. Moreover, amphetamine, a dopamine agonist, and MK801, a NMDA antagonist, were used to assess VP modulatory activity on dopaminergic and glutamatergic PPI, social interaction and ERP impairments. BRAT rats had reductions in vocal communication beginning at post natal day 9. Additionally, BRAT rats had deficits in low and high gamma inter-trial coherence and N40 amplitude. Furthermore, MK801-induced impairments in behavioral and electrophysiological measures were consistent in control and BRAT rats suggesting minimal modulatory activity of vasopressin on NMDA signaling. In contrast, amphetamine-induced deficits were genotype dependent. In control animals, amphetamine caused PPI and social interaction deficits whereas there was no effect in BRAT rats. In addition, ERP components were unaltered in control rats, whereas N40 amplitude, evoked gamma power, and gamma signal to noise ratio were all elevated. These results indicate that the role of VP on vocal communication is an age dependent process and the deficits in ERPs indicate a neuromodulatory role of VP. Based on behavioral and electrophysiological evidence, vasopressin likely does not modulate glutamatergic signaling. On the contrary, the vasopressin and dopamine interaction is likely highly complex and future studies are necessary to comprehend this modulatory relationship.