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PhD Thesis: Monica Arnold

Dissertation Abstract:
Influence of Monoamine Oxidase Inhibition on Nicotine Self-Administration

By Monica Martin Arnold
Doctor of Philosophy in Pharmacology and Toxicology
University of California, Irvine, 2011
Professor Frances M. Leslie, Chair

Despite the clear health risks from tobacco use, cessation rates are low and relapse rates are high. Most prior research has focused on nicotine, the main psychoactive constituent of tobacco smoke, in adult male animal models. However, nicotine has been found to be weakly reinforcing compared to other drugs of abuse.

Furthermore, there are over 7,000 other tobacco smoke constituents, including those that inhibit the enzyme, monoamine oxidase (MAO). It has been suggested that MAO inhibitors may interact with nicotine to contribute to tobacco addiction. Smoking initiation generally begins during adolescence, a critical period of brain development and plasticity, which may result in particular vulnerability to the effects of tobacco. Furthermore, women have been shown to express different smoking behaviors and may be more susceptible to negative aspects of smoking, including withdrawal. Thus, the predominant experimental model may not accurately depict smoking in these distinctive populations. The aim of this dissertation was therefore to test the hypothesis that discrepancies observed between the clinical and preclinical findings are a result of limitations of the principal self-administration animal model that is currently used.

To model interactions between MAO inhibitors and nicotine, the clinically available MAO inhibitor, tranylcypromine (TCP), was administered peripherally prior to behavioral testing. TCP inhibited MAO similarly in adult males, females and adolescent males and enhanced nicotine reinforcement in all groups. However, enhanced reinforcement in females and adolescents appeared to result from acute, monoamine release induced by TCP rather than from MAO inhibition. In separate studies, the reinforcing effect of norharmane, an MAO inhibitor found in smoke, was studied. Norharmane alone was reinforcing in male adults and adolescents, but not in adult females. However, norharmane exposure influenced female estrous cycle phase. In contrast, nicotine+norharmane was reinforcing in adult males and females, and produced additive reinforcement at higher reinforcement schedules in males. Neuroanatomical studies indicated that self-administration of nicotine, norharmane and nicotine+norharmane resulted in distinct regional cfos expression patterns and correlations with behavior. Together, these data provide strong behavioral and neuroanatomical evidence for limitations of nicotine self-administration in adult males as a model for tobacco use.