Stress is a major factor that promotes tobacco use and relapse during withdrawal. Although women are more vulnerable to tobacco use than men, the manner in which stress contributes to tobacco use in women versus men is unclear. Thus, the goal of this study was to compare behavioral and biological indices of stress in male and female rats during nicotine withdrawal. Since the effects of nicotine withdrawal are age-dependent, this study also included adolescent rats. An initial study was conducted to provide comparable nicotine doses across age and sex during nicotine exposure and withdrawal. Rats received sham surgery or an osmotic pump that delivered nicotine. After 14 days of nicotine, the pumps were removed and controls received a sham surgery. Twenty-four hours later, anxiety-like behavior and plasma corticosterone were assessed. The nucleus accumbens (NAcc), amygdala, and hypothalamus were examined for changes in corticotropin-releasing factor (CRF) gene expression. In order to differentiate the effects of nicotine withdrawal from exposure to nicotine, a cohort of rats did not have their pumps removed. The major finding is that during nicotine withdrawal, adult females display higher levels of anxiety-like behavior, plasma corticosterone, and CRF mRNA expression in the NAcc relative to adult males. However, during nicotine exposure, adult males exhibited higher levels of corticosterone and CRF mRNA in the amygdala relative to females. Adolescents displayed less nicotine withdrawal than adults. Moreover, adolescent males displayed an increase in anxiety-like behavior and an up-regulation of CRF mRNA in the amygdala during nicotine exposure and withdrawal. These findings are likely related to stress produced by the high doses of nicotine that were administered to adolescents to produce equivalent levels of cotinine as adults. In conclusion, these findings suggest that intense stress produced by nicotine withdrawal may contribute to tobacco use in women.

This study examined the impact of emotion on opiate withdrawal induced hyperalgesia to determine whether emotional states modulate the magnitude of hyperalgesia. One hundred Hispanic males were recruited into one of three groups: heroin withdrawal, long-term heroin abstinence, and controls. Participants were presented with pictures to induce neutral, positive and negative emotional states. Affective valence, arousal, pain threshold and tolerance to ischemic pain were measured. When pain threshold and tolerance were compared, the withdrawal group displayed significant heightened pain sensitivity when negative affect was induced. We also found that former heroin addicts showed heightened pain sensitivity following months of abstinence.

IntroductionTobacco use is the number one cause of preventable deaths in the United States. 1 Of particular concern is the high rate of tobacco use among women, who are more susceptible to the negative health consequences of long-term smoking than men. 2 As a result, tobacco use is believed to be a major contributing factor to health disparities in women. In spite of the magnitude of the problem, surprisingly little is known about the underlying biological factors that promote tobacco relapse in females.Much work has suggested that stress promotes tobacco use in women. For example, women report more negative mood states, such as depression, anxiety, and intense craving during smoking abstinence than men. [3][4][5] Women also use more tobacco products and display lower quit rates relative to men. 6 Furthermore, women report that they maintain tobacco use to relieve intense withdrawal symptoms that emerge during abstinence, and they claim more often than men that the anxiety-reducing effects of cigarettes are the main reason for smoking. [7][8][9] Preclinical studies have shown that the behavioral and biological consequences of nicotine withdrawal are greater in female versus AbstractIntroduction: Previous work led to our hypothesis that sex differences produced by nicotine withdrawal are modulated by stress and dopamine systems in the nucleus accumbens (NAcc). We investigated our hypothesis by studying intact females to determine whether the mechanisms that promote withdrawal are ovarian-hormone mediated. Methods: Female rats were ovariectomized (OVX) or received sham surgery (intact) on postnatal day (PND 45-46). On PND 60, they received sham surgery (controls) or were prepared with nicotine pumps. Fourteen days later, half of the rats had their pumps removed (nicotine withdrawal) and the other half received sham surgery (nicotine exposure). Twenty-four hours later, the rats were tested for anxiety-like behavior using the elevated plus maze and light/dark transfer procedures. The NAcc was then dissected for analysis of several genes related to stress (CRF, UCN, CRF-R1, CRF-R2, CRF-BP, and Arrb2) or receptors for dopamine (Drd1 and Drd2) and estradiol (Esr2). Results: During withdrawal, intact females displayed an increase in anxiety-like behavior in both tests and CRF, UCN, and Drd1 gene expression. During nicotine exposure, intact females displayed a decrease in CRF-R1, CRF-R2, Drd3, and Esr2 gene expression and an increase in CRF-BP. This pattern of results was absent in OVX females. Conclusions: Nicotine withdrawal produced an increase in anxiety-like behavior and stress-associated genes in intact females that is distinct from changes produced by nicotine exposure. The latter effects were absent in OVX females, suggesting that stress produced by withdrawal is ovarianhormone mediated. These findings have important implications towards understanding tobacco use liability among females.