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PhD Thesis: Wei Si

Dissertation Abstract:
Potential Roles of Neuropeptide S in the Pathophysiology of Schizophrenia

By Wei Si
Doctor of Philosophy in Pharmacology and Toxicology
University of California, Irvine, 2012
Dr. Rainer K. Reinscheid, Chair

The aim of the studies presented in this dissertation is to investigate the potential roles of the Neuropeptide S (NPS) system in emotional and cognitive processing and pathophysiology of schizophrenia. NPS and its cognate receptor NPSR constitute a recently identified neuropeptide system, but their physiological functions remain unclear.

The aim in Chapter 2 is to investigate the effect of NPS on the release of dopamine and serotonin in the medial prefrontal cortex (mPFC), an area crucial for emotional and cognitive processing, by in vivo microdialysis in rats. Centrally administered NPS dose-dependently enhanced extracellular levels of dopamine and its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), whereas no effect on serotonergic transmission was detected. Prefrontal cortical dopamine has been linked to modulation of anxiety state and fear extinction. The present results provide a physiological and anatomical basis for the anxiolytic activity of NPS and its stimulatory effect on fear extinction. Moreover, low cortical dopamine levels are thought to be responsible for the negative symptoms of schizophrenia. Therefore, the present findings also suggest that NPS may possess antipsychotic activity by enhancing dopamine neurotransmission in the mPFC.

The aim in Chapter 3 is to investigate potential antipsychotic effects of the NPS system using the prepulse inhibition (PPI) paradigm. Previous studies have examined the interaction of the NPS system with glutamatergic neurotransmission and the effects of enhanced NPS signaling on MK-801-induced neuropathological, neurochemical, and behavioral symptoms, suggesting that NPS might have potential antipsychotic activity. Results from the present study indicate that NPSR deficiency induced PPI deficits and aggravated MK-801-induced PPI disruption in male, but not female, mice independent of strain during late adolescence through young adulthood. Also, atypical antipsychotic clozapine was found to reverse PPI disruption associated with NPSR deficiency. Additionally, the NPS system may play a role in modulation of PPI by, at least in part, regulating attentional control. The present observations validate the NPS system as an attractive target for the development of novel antipsychotics.