Abstract
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.
Highlights
Epidemiological reports have indicated that women are more susceptible to tobacco use as compared to men (Perkins, 2009; Lombardi et al, 2011; Rahmanian et al, 2011)
Regarding age differences during nicotine exposure, adults displayed higher cotinine levels than adolescents prepared with one small pump and adolescents re-implanted with one small pump that was adjusted for weight gain [F (3, 79) = 8.96, P < 0.05]
A similar pattern was observed during nicotine withdrawal, such that similar levels of cotinine were observed in adults and adolescents that were implanted with two small pumps that each delivered a nicotine dose of 4.7 mg/kg/day
Summary
Epidemiological reports have indicated that women are more susceptible to tobacco use as compared to men (Perkins, 2009; Lombardi et al, 2011; Rahmanian et al, 2011). During abstinence from tobacco, women report more intense symptoms of withdrawal than men (Heishman et al, 2010; Nakajima and al’Absi, 2012; Perkins et al, 2013). There is evidence to suggest that the enhanced susceptibility to tobacco use in women begins at a young age. During abstinence from tobacco, adolescent females report higher levels of stress and relapse rates as compared to adolescent males (Anderson and Burns, 2000; Colby et al, 2000; Dickmann et al, 2009). Despite the magnitude of this problem, there is a critical knowledge gap regarding the factors that contribute to enhanced vulnerability to tobacco use among women
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