Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

5-2012

Committee Chair or Co-Chairs

Russell W. Brown

Committee Members

Ronald H. Baisden, Theresa A. Harrison, David S. Roane, Brooks B. Pond, Gregory A. Ordway

Abstract

Schizophrenia affects about 1% of the population. A hallmark of the disorder is increased dopamine D2 receptor sensitivity in the brain. Studies have shown that schizophrenics smoke cigarettes at approximately 4 times the rate of the general population. It has been suggested that nicotine use is a form of self-medication for symptoms in schizophrenia. Smoking behaviors typically begin in adolescence. We assessed effects of nicotine on behavior and brain plasticity in an adolescent rodent model of schizophrenia with the goal of identifying targets for smoking cessation. Methods: Rats were neonatally treated with quinpirole (a D2/D3 agonist) or saline and sensitized to 0.3, 0.5, or 0.7 mg/kg (free base) nicotine or saline, every other day for 9 days, and locomotor activity was recorded. After behavioral testing, animals demonstrating sensitization to 0.5mg/kg nicotine were surgically implanted with a guide cannula, aimed at the nucleus accumbens core. After recovery, animals underwent microdialysis and in vivo samples were collected every 20 minutes for 300 minutes. Postmortem brains from animals exposed to 0.5mg/kg nicotine or saline were dissected and the nucleus accumbens and dorsal striatum were analyzed for brain-derived neurotrophic factor (BDNF), phosphorylated cAMP response element binding protein (pCREB), and glial-cell derived neurotrophic factor (GDNF), all proteins involved in neuronal plasticity. Results: Animals neonatally treated with quinpirole and administered nicotine showed robust increases in locomotor sensitization and a 400% increase in dopamine overflow from the accumbens core, which was greater than all other groups. Nicotine administration led to increased accumbal BDNF levels, which was enhanced by neonatal quinpirole pretreatment. GDNF levels were also increased in control animals given nicotine, which was attenuated to control levels by neonatal quinpirole. Finally, pCREB levels were robustly increased in animals neonatally treated with quinpirole, an effect that was partially attenuated by adolescent nicotine treatment. These data on pCREB suggest a possible biological marker of anhedonia. In conclusion, it is apparent that nicotine results in a robust increase in behavioral activity and changes in neural proteins of brain plasticity that may serve as possible pharmaceutical targets for smoking cessation in schizophrenia.

Document Type

Dissertation - unrestricted

Copyright

Copyright by the authors.

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