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Abstract
Introduction: To date, anticholinesterase therapy is the mainstay of treatment for Alzheimers disease, but offers a limited effect on cognitive function. This therapeutic approach is based on extensive work conducted in the 1970s and 1980s that led to the cholinergic hypothesis, which focuses on the important role of the major neurotransmitter, acetylcholine. The central hypothesis of the following studies was that repeated exposure to nicotine, the prototypical nicotinic acetylcholine receptor agonist, would have a positive effect on (1) performance in a learning task, (2) the expression of central nicotinic acetylcholine receptors, (3) central nerve growth factor protein levels and (4) cell proliferation in the hippocampal formation with learning. The rationale for these studies was that a comprehensive investigation of how repeated nicotine exposure specifically affects brain plasticity would facilitate future studies in the design of nicotine analogs with enhanced specificity to targets mediating its beneficial effects and decreased specificity to targets mediating its adverse side effects. Methods: Male Wistar rats were exposed to nicotine (0.7 mg/kg/day) for 14 days and memory function was evaluated with two types of water maze methods, then brains were processed for receptor autoradiography, immunoblotting, ELISA and immunohistochemistry. Results: Rats treated with nicotine demonstrated: (1) improved water maze performance, (2) an increase in high affinity nicotinic and M2 muscarinic acetylcholine receptors, (3) an increase in the expression of hippocampal TrkA receptors, cholinergic markers and proliferating cells (with learning). Discussion: The results of these experiments suggest that in addition to improving memory task performance, nicotines neurotrophic effects may be mediated through its interaction with the cholinergic and nerve growth factor system, and perhaps central proliferative zones. Conclusions: All together, the results of this doctoral dissertation add to a growing body of information about the positive effects of nicotine on brain plasticity. The significance of these positive changes is that many of the factors improved with nicotine exposure are also compromised and implicated in the pathogenesis of neurodegenerative diseases (i.e. Alzheimers disease).