Nicotine Withdrawal Increases Stress-Associated Genes in the Nucleus Accumbens of Female Rats in a Hormone-Dependent Manner

Abstract

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.

Estradiol promotes the rewarding effects of nicotine in female rats

“…In order to assess the role of E2 in modulating the rewarding effects of nicotine, we removed ovarian tissue and immediately began an E2 supplementation procedure. The OVX procedure was done at PND 45-46 based on previous work in our laboratory showing that adult female rats that received OVX procedures at PND 45 display a reduction in the rewarding effects of nicotine [14] and a suppression of anxiety-like behavior and stress-associated gene expression during nicotine withdrawal [23-24]. These studies suggest that after PND 45 ovarian hormones play a key role in modulating the behavioral effects and molecular changes produced by nicotine.…”

Insight into the Potential Factors That Promote Tobacco Use in Vulnerable Populations

“…These studies suggest that nicotine withdrawal induces similar physical signs in females and males; however, the negative affective states induced by withdrawal is larger in females. The latter effect appears to be modulated via ovarian hormones, as ovariectomized (OVX) females do not display anxiety-like behavior during withdrawal [57]. In summary, these studies suggest that both nicotine reward and withdrawal are greater in females as compared to males.…”

“…Recently, we postulated that nicotine withdrawal induces a larger increase in CRF and, as a result, a larger decrease in dopamine in the NAcc in females as compared to males [57]. This hypothesis is based on our finding that adult females display a larger increase in dopamine (D1) receptor mRNA levels in the NAcc than males [57]. The latter result is believed to serve as indirect evidence that dopamine levels are lower in the NAcc of females versus males during withdrawal.…”

“…However, intra-NAcc CRF administration produces CPA and a reduction in dopamine levels in chronically stressed rats. Recently, we postulated that nicotine withdrawal induces a larger increase in CRF and, as a result, a larger decrease in dopamine in the NAcc in females as compared to males [57]. This hypothesis is based on our finding that adult females display a larger increase in dopamine (D1) receptor mRNA levels in the NAcc than males [57].…”

“…Adolescent rats were also resistant to the decreases in NAcc dopamine levels produced by administration of a kappa agonist in nicotine-dependent rats [84]. Subsequent studies revealed that adolescent and adult rats display similar increases in ACh levels [85] and stress-associated genes [57] in the NAcc during nicotine withdrawal. Taken together, these studies suggest that age differences produced by nicotine withdrawal are modulated via NAcc dopamine systems.…”