Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

5-2020

Committee Chair or Co-Chairs

Russell W. Brown

Committee Members

Richard M. Kostrzewa, Gregory A. Ordway, Matthew I. Palmatier, Diego Rodriguez-Gil

Abstract

Quinpirole is a dopamine D2 receptor agonist that if administered to rats from postnatal day (P)1-21 results in increased dopamine D2 receptor sensitivity throughout the animal’s lifetime. This increase in receptor sensitivity is consistent with schizophrenia. This model has additional consistencies with human schizophrenia, including sensorimotor gating deficits, enhanced behavioral and neurobiological responses to nicotine, and protein alterations consistent with the disorder. In this study, a second generation of the neonatal quinpirole (NQ) rodent model was created to investigate if long term changes caused by NQ treatment would be passed to offspring. NQ treated rats were mated and their offspring left untreated. To investigate if dopamine D2 receptor hypersensitivity was transmitted from the first to the second generation of the model, yawning behavior was assayed after acute quinpirole treatment. Prepulse inhibition (PPI) is a test of sensorimotor gating, and PPI testing was performed on adolescent second generation rats. Behavioral sensitization and conditioned place preference to nicotine (0.5 mg/kg and 0.6 mg/kg respectively) were examined in adolescence in both generations of the model. Several neurobiological assays were performed in both nicotine naïve and animals sensitized to nicotine (0.5 mg/kg) in order to investigate consistencies with the NQ model, which has shown enhanced responses to nicotine. These include enzyme linked immunosorbent assays (ELISAs) for brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB), as well as quantitative PCR (qPCR) to quantify messenger RNA (mRNA) of regulator of G-protein signaling 9 (rgs9). Results indicated that second generation rats of NQ-treated rats demonstrated increased yawning behavior in response to acute quinpirole treatment. PPI deficits and enhanced behavioral responses to nicotine were also observed. Increased BDNF expression was observed in the nucleus accumbens following nicotine sensitization, consistent with past work in first generation NQ-treated rats. CREB expression was also increased in both generations of the model, an effect linked to alterations in PPI and other schizophrenia-like symptomology. Rgs9 expression was generally unaltered in either generation of the model. This study provides basis for utilization of a second generation of the NQ model to study epigenetic influences in schizophrenia and drug abuse vulnerability.

Document Type

Dissertation - embargo

Copyright

Copyright by the authors.

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