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Document Type

Dissertation - University Access Only

Award Date

2014

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Shafiqur Rahman

Abstract

Major depression affects about one-sixth of US population. Nearly one-third of depressed patients are addicted to drugs of abuse including alcohol or nicotine. Brain nicotinic acetylcholine receptors (nAChRs) have emerged as an important target for major depression as well as chronic use of alcohol (ethanol) and nicotine. We hypothesized that brain β2-containing nAChR subtypes are critically involved in regulating the behavioral, cellular and molecular mechanisms underlying major depression associated with chronic effects of ethanol and nicotine. Therefore, primary goal of the present study was to determine the role of brain nAChRs in regulating the behavioral, cellular, and molecular mechanisms involved in major depression-like behavior associated with ethanol or nicotine taking behavior using validated mouse models. We have demonstrated that systemic administration of β2-selective or nonselective nAChR antagonists including lobeline significantly reduced depression-like behavior in mice. Lobeline also decreased plasma corticosterone levels and attenuated norepinephrine levels in the prefrontal cortex. Our results indicated the important role of β2-containing nAChR-mediated signaling in neurotransmitter and neuroendocrine imbalance in major depression. Further, chronic lobeline treatment prevented downregulation of brain-derived neurotrophic factor (BDNF) expression and reduction in hippocampal cell proliferation following chronic unpredictable stress, an animal model of depression. Our data suggested that β2-containing nAChR mediated signaling is involved in neuroplastic changes that are characteristics of major depression. Moreover, co-administration of lobeline significantly increased the antidepressant-like effects of commonly used antidepressants, such as reboxetine or bupropion. The results suggested that blockade of β2-containing nAChRs mediated signaling may enhance the efficacy of antidepressants that inhibit reuptake of norepinephrine or dopamine. We have also shown that lobeline treatment reduced chronic ethanol-induced increased depression-like behavior, hippocampal serotonin levels, and cell proliferation in the dentate gyrus of hippocampus. Similarly, chronic nicotine-induced enhanced depression-like behavior, elevation of norepinephrine and BDNF levels in the hippocampus were prevented by lobeline treatment. Taken together, our results provided strong evidence that β2-containing nAChR subtypes mediated signaling regulate behavioral, cellular and molecular mechanisms involved in major depression-like behavior and associated with chronic ethanol or nicotine exposure.

Library of Congress Subject Headings

Nicotinic receptors
Depression, Mental
Ethanol -- Physiological effect
Nicotine -- Physiological effect

Description

Includes bibliographical references (pages 150-197)

Format

application/pdf

Number of Pages

214

Publisher

South Dakota State University

Rights

In Copyright - Non-Commercial Use Permitted
http://rightsstatements.org/vocab/InC-NC/1.0/

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