Date of Award


Degree Name

Doctor of Philosophy




Laura E. O'Dell


Introduction: Tobacco use is a major economic and health problem. Particularly concerning is that women consume more tobacco products, have a more difficult time quitting, and are less likely to benefit from cessation therapies than men. As a result, women are at higher risk of developing tobacco-related diseases. Women are generally more susceptible to stress and are more likely to cope with stress by smoking as compared to men. During abstinence, women also experience intense anxiety as compared to men and report that the anxiety-reducing effects of smoking are the main reason for continued use and relapse. Thus, stress produced by nicotine withdrawal may enhance susceptibility to tobacco use and relapse in female versus male smokers. Although cessation approaches focus on alleviating withdrawal, the contribution of anxiety produced by withdrawal to tobacco use in females is unclear.

Methods: The present study compared sex differences in various behavioral and biological indices of stress during nicotine exposure and withdrawal from this drug. Potential sex differences in these measures were also compared during adolescence. Briefly, male and female adolescent and adult rats underwent sham surgery or received subcutaneous implantation of pumps that delivered nicotine. Fourteen days later, the pumps were either removed to induce withdrawal or were left in place in order to examine the effects of nicotine exposure. Twenty-four hours later, anxiety-like behavior was assessed using elevated plus maze and open field tests. Blood samples were also collected and analyzed for corticosterone, a biological marker of stress. Brain tissue from the nucleus accumbens (NAcc), amygdala, and hypothalamus were examined for changes in corticotropin-releasing hormone (CRH) gene expression. Potential group differences in nicotine metabolism were assessed via measurements of cotinine (a nicotine metabolite) during nicotine exposure and withdrawal.

Results: During withdrawal, adult females displayed higher levels of anxiety-like behavior, plasma corticosterone, and CRH gene expression in the NAcc relative to adult males. During nicotine exposure; however, adult males exhibited higher levels of corticosterone and CRH gene expression in the amygdala. These sex differences are not related to nicotine metabolism, since male and female adult rats displayed similar cotinine levels during nicotine exposure and withdrawal. Adolescent males displayed an increase in anxiety-like behavior and an up-regulation of CRH mRNA expression in the amygdala during exposure and withdrawal from nicotine. These findings are likely related to stress produced by the high doses of nicotine that were administered to the adolescents to produce equivalent levels of cotinine as adults.

Conclusion: The results show that there are sex differences in stress responses produced by nicotine exposure versus withdrawal from this drug. Of particular clinical relevance, these findings show that female adults display greater behavioral and biological indices of stress during nicotine withdrawal than males. Thus one plausible underlying substrate by which adult females are more vulnerable to tobacco use may be intense stress produced by nicotine withdrawal as compared to males. This work reflects an important first step toward developing effective smoking cessation strategies for treating tobacco use among women. Importantly, the pattern of changes during nicotine exposure and withdrawal were different in adult versus adolescent rats, suggesting important developmental differences that should be considered when developing smoking cessation treatments for different age groups.




Received from ProQuest

File Size

108 pages

File Format


Rights Holder

Oscar Valentin Torres