Reductions in the levels of the neuropeptide vasopressin (VP) and its receptors have been associated with schizophrenia. VP is also critical for appropriate social behaviors in humans as well as rodents. One of the prominent symptoms of schizophrenia is asociality and these symptoms may develop prodromally. A reduction in event-related potential (ERP) peak amplitudes is an endophenotype of schizophrenia. In this study, we use the Brattleboro (BRAT) rat to assess the role of VP deficiency in vocal communication during early development and on auditory ERPs during adulthood. BRAT rats had similar vocal communication to wild-type littermate controls during postnatal days 2 and 5 but the time between vocalizations was increased and the power of the vocalizations was reduced beginning at postnatal day 9. During adulthood, BRAT rats had deficits in auditory ERPs including reduced N40 amplitude and reduced low and high gamma intertrial coherence. These results suggest that the role of VP on vocal communication is an age-dependent process. Additionally, the deficits in ERPs indicate an impairment of auditory information processing related to the reduction in VP. Therefore, manipulation of the VP system could provide a novel mechanism for treatment for negative symptoms of schizophrenia.

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Background: The vasopressin deficient Brattleboro (BRAT) rats have behavioral impairments which mimic those seen in other schizophrenia models. 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 those observed in the BRAT rats. Therefore, a potential mechanism for vasopressin induces behavioral abnormalities could be through modulation of dopamine or glutamate signaling. Consequently, the aim of this study was to assess the modulatory function of vasopressin on dopamine and NMDA signaling. Methods: Single intraperitoneal injection of amphetamine (0.5 mg/kg), a dopamine agonist, and MK801 (0.25 mg/kg), a NMDA antagonist, were used to assess vasopressin (VP) modulatory activity on dopaminergic and glutamatergic pre-pulse inhibition of startle (PPI), social interaction and auditory event related potential (ERPs) impairments in BRAT and littermate control WT rats. Results: MK801-induced impairments were consistent and not significantly different between WT 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 a statistically significant deficit in PPI and social interaction whereas there was no effect in BRAT rats. Conversely, ERP components were unaltered in control rats, whereas N40 amplitude, evoked gamma power, and gamma signal to noise ratio were all elevated in BRAT rats. Conclusions:The ERP component analyses of BRAT rats treated with amphetamine suggest modulation of auditory information processing through interplay between dopaminergic and vasopressin. However, the behavioral and electrophysiological evidence presented here also suggest that vasopressin does not modulate glutamatergic signaling through NMDA receptors. Further evidence in necessary to determine the interaction between vasopressin and dopamine signaling and future studies are necessary to comprehend glutamatergic interactions with vasopressin that are not NMDA-mediated.