Examining the Behavioral and Molecular Aspects of Adolescent Nicotine Dependence: Implications for Vulnerability to Drugs of Abuse

EXAMINING THE BEHAVIORAL AND MOLECULAR ASPECTS OF ADOLESCENT NICOTINE DEPENDENCE: IMPLICATIONS FOR VULNERABILITY TO DRUG ABUSE By Dena Heath Kota, B.S. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2008 Major Director: M. Imad Damaj, Ph.D Associate Professor, Pharmacology and Toxicology Approximately 200 million men and 100 million women smoke worldwide. In the United States, an estimated 25.9 million men (23.9 percent) and 20.7 million women (18.1 percent) are smokers. The commencement of smoking at a young age is thought to increase addiction liability, decrease the probability of successful cessation, and correlate with a higher number of cigarettes smoked per day. Studies from the World Health Organization indicate that between 80,000 and 100,000 children start smoking every day worldwide. These statistics suggest that adolescence is a critical phase for developing nicotine dependence. The work in this dissertation contributes to the further xiii understanding of this unique developmental period. Our research shows that various aspects of nicotine dependence are both ageand sex-dependent. We observed ageand sex-related differences in both nicotine reward and withdrawal models that imply a heightened vulnerability for adolescents. In addition, we have investigated possible behavioral and molecular mechanisms which may underlie the elevated vulnerability to dependence. The data illustrate that while behavioral mechanisms only play a minor role in the differences seen in reward and withdrawal, molecular mechanisms appear to have a greater contribution. Specifically, increased nicotinic receptor function is likely to be a substantial contributor to age-related disparities. In addition, nicotine is one of the first and most commonly abused drugs in adolescence and is known to be a strong predictor of subsequent alcohol and other drug abuse. Our research investigated the effects of adolescent nicotine exposure on both nicotine and cocaine dependence in adulthood. We found that exposure to nicotine during the early phase of adolescence affects both nicotine reward and withdrawal in adulthood. Moreover, this exposure also bears impact on other drugs of abuse such as cocaine. In summary, our data suggest that early adolescence is the most critical period for becoming dependent to nicotine and that early experimentation with nicotine may lead to enhanced vulnerability to dependence on more illicit drugs of abuse. It is imperative that we understand why adolescents have a heightened susceptibility to nicotine dependence so that better smoking cessation therapies and prevention messages can be developed for this age group. GENERAL INTRODUCTION A. Tobacco Smoking and Nicotine Dependence In the United States, an estimated 25.9 million men (23.9 percent) and 20.7 million women (18.1 percent) are smokers (National Health Interview Survey (NHIS), 2005, National Center for Health Statistics). More importantly, smoking relateddiseases kill one in ten adults globally, or cause four million deaths. By 2030, if current trends continue, smoking will kill one in six people (World Health Organization Smoking Statistics 2002). Nicotine addiction is not only a problem for the adult population. Surprisingly, over 6,000 teenagers begin smoking every day (American Lung Association Statistics 2002). Moreover, 90% of adult smokers report their first use of tobacco prior to age 18 (Chassin et al. 1990). Tobacco is reportedly the most avoidable cause of disease and disability, yet less than 7% of smokers who attempt to quit actually achieve more than one year of abstinence before they relapse (NIH Pub. No. 98-4342, CDC Prevention and Health Promotion, 2005). Smoking is a significant and preventable health concern that needs further attention so that sophisticated health promotion campaigns and messages can be imparted to the public. Nicotine is the primary addictive component in tobacco that acts on the brain to produce both rewarding and aversive effects (Castane et al. 2005). Although nicotine is known to reach the brain rapidly, it does not have long lasting acute effects due to its short half-life of 1-2 hours (Viveros et al. 2006). This property of nicotine is likely to contribute to its repeated and consistent use. In addition, environmental cues play an