PhD (Doctor of Philosophy)
Date of Award
Committee Chair or Co-Chairs
Russell W. Brown, Matthew I. Palmatier
John R. Webb, Eric W. Sellers, Richard Kostrzewa
The current study was designed to analyze the roles of both α7 and α4β2 nicotinic receptors (nAChRs) in behavioral sensitization and its effects on Brain Derived Neurotrophic Factors (BDNF) and the mammalian target of rapamycin (mTOR) in the neonatal quinpirole model of schizophrenia. Animals were treated neonatally with either quinpirole (1 mg/kg) or saline starting on P1 and treatment persisted through P21. Starting on P33, animals were sensitized to nicotine (0.5 mg/kg free base) every other day up to P49. Following sensitization, brains were harvested at 1 h and 24 h post-drug treatment and BDNF protein and total mTOR activity were assessed in the nucleus accumbens. Results revealed that α7 antagonism failed to block nicotine sensitization regardless of neonatal quinpirole treatment, and appears to block the initial hypoactive response to nicotine in males but not females. In addition, α7 antagonism effectively blocked the enhanced BDNF response to nicotine in both saline and quinpirole treated animals but was ineffective at blocking mTOR at the 1 h time point, and resulted in decreases of mTOR at the 24 h time point. Antagonism of the α4β2 nAChR effectively blocked nicotine sensitization in both males and females but the higher dose resulted in a significant initial hypoactive response to nicotine. In addition, α4β2 nAChR antagonism blocked nicotine induced increases in BDNF. Total mTOR revealed that neonatal quinpirole produced a decrease in mTOR that was reversed by nicotine at the 1h but not the 24h time point and antagonism of nAChRs resulted in sex dependent effects. There results have implication towards the mechanisms underlying enhanced smoking in schizophrenia.
Dissertation - Withheld
Peterson, Daniel, "The Effects of Nicotine in the Neonatal Quinpirole Rodent Model of Schizophrenia: Neural Plasticity Mechanisms" (2016). Electronic Theses and Dissertations. Paper 3083. http://dc.etsu.edu/etd/3083
Copyright by the authors.