Elsevier

Physiology & Behavior

Volume 203, 1 May 2019, Pages 33-41
Physiology & Behavior

Exercise or saccharin during abstinence block estrus-induced increases in nicotine-seeking

https://doi.org/10.1016/j.physbeh.2017.10.026Get rights and content

Highlights

  • In females, treatment outcome for nicotine addiction may depend on hormonal status.

  • We compared the efficacy of exercise vs saccharin during abstinence on nicotine-seeking.

  • Efficacy was examined as a function of estrous cycle phase.

  • Both exercise and saccharin blocked estrus-induced increases in nicotine-seeking.

  • Exercise or enrichment may effectively reduce nicotine craving in human females.

Abstract

Recent evidence suggests that adolescent and young adult females may be particularly responsive to nicotine use interventions that include exercise or environmental enrichment. This possibility was addressed in the current study by comparing the efficacy of exercise versus non-exercise environmental enrichment (saccharin) during abstinence at reducing subsequent nicotine-seeking/relapse vulnerability in an adolescent-onset rat model. The efficacy of each intervention was examined as a function of estrous cycle phase given findings indicating that hormonal status influences relapse vulnerability and treatment outcome in females. Once adolescent female rats acquired nicotine self-administration, they were given 23-h/day access to nicotine (0.01 mg/kg/infusion) for 10 days. Following the last self-administration session, rats began a 10-day forced abstinence period with 2-h/day access to an unlocked wheel (exercise, n = 15), a bottle containing a saccharin-sweetened solution (0.25%; saccharin, n = 19), or without access to a wheel or saccharin (control, n = 20). Nicotine-seeking, as assessed under an extinction/cued-induced reinstatement procedure, was examined on day 11 of abstinence. Levels of nicotine-seeking were highest in females tested during estrus as compared to females tested during non-estrus phases. Exercise or saccharin during abstinence reduced nicotine-seeking in females tested during estrus, but neither affected the low levels of nicotine-seeking observed in females tested during non-estrus phases, presumably due to a floor effect. These results demonstrate that exercise or saccharin during abstinence decrease nicotine-seeking, and suggest that either would be effective as an early intervention for nicotine use and addiction in females.

Introduction

Tobacco use is the leading cause of preventable death in the United States, with 1 of every 5 deaths attributable to smoking [68]. Most smokers initiate use during adolescence, and although 80% of smokers report wanting to quit, very few are successful at doing so [68]. The tobacco industry spends billions of dollars each year on advertisements, promotions, and product development to encourage tobacco use, focusing particularly on adolescents [15]. These efforts have been effective: > 2% of middle school students and 9% of high school students report current cigarette use [10], [27]. Rates of e-cigarette use are even higher, having surpassed rates of cigarette use in 2014, with > 5% of middle school students and 16% of high school students reporting current e-cigarette use [10], [27]. These trends are expected to continue with this cohort into adulthood and throughout their lifetime [67]. Adolescent tobacco and nicotine use has also been shown to be predictive of illicit drug use in adulthood [28], [29], [35]. Therefore, early intervention may be critical for not only preventing the progression of nicotine addiction into adulthood, but also for reducing the risk of illicit drug use and abuse.

Early nicotine use intervention may be particularly beneficial for females. Although women have historically maintained lower rates of tobacco use as compared to men, sex differences have narrowed over time [2], [42], [46], and among adolescent populations, rates of current smoking are now equivalent between females and males (ages 12 to 17; 8.4% versus 8.9%, respectively; [22]). These findings are significant considering that females are at greater risk for tobacco-related diseases as compared to males [4], [66]. Female smokers are also less likely than male smokers to try to quit smoking, and are more likely to relapse when they do attempt to quit [2], [4], [49], [50]. Preclinical results corroborate an enhanced vulnerability in females with results showing that adolescent and adult female rats acquire nicotine self-administration faster, are more motivated to obtain nicotine, and self-administer higher levels of nicotine under extended access conditions as compared to their male counterparts [13], [36], [38], [58]. These parallel findings suggest that the enhanced vulnerability in females is biologically based, and indicate the utility of preclinical studies using adolescent females for identifying interventions for nicotine addiction in this vulnerable population.

Interventions aimed at reducing nicotine use and addiction typically focus on replacing or mimicking the effects of nicotine, the primary addictive component in tobacco products. However, such pharmacological approaches are not very effective for females [48], and are not feasible for adolescents due to concerns with ongoing brain development [30]. Exercise has been suggested as a non-pharmacological intervention for nicotine addiction that may be particularly suited as an intervention for females ([41]; also see [6], [47], [53]). For example, the weight control benefits of exercise may be particularly attractive to girls/young women who report weight gain concerns as a significant contributor to maintenance smoking and relapse to smoking [20], [25], [63]. Females also experience greater negative affect during nicotine withdrawal, and are more likely to attribute relapse to withdrawal relief or to reduce stress or negative affect as compared to men [4], [43]. Exercise is known to decrease anxiety and nicotine withdrawal severity [5], [6], [52], [55]; thus, individuals may be able to mimic the anxiolytic effects of smoking with exercise.

Although few studies have specifically examined exercise as an early intervention for nicotine addiction in girls/young adult females, recent findings in women and adult populations that include women support its potential efficacy (for review see [41]). For example, numerous studies have shown that exercise during abstinence reduces cigarette craving and the likelihood of relapse [23], [55], [74], and improves treatment outcome when used as an adjunct to other treatments [6], [47], [65], [73]. Results from preclinical studies also support the potential utility of exercise as an intervention for drug addiction including nicotine addiction [45], [51], [57], [58], [59], [60], [75]. For example, we showed in an adolescent-onset model of nicotine addiction that wheel-running exercise (2-hr/day) during forced abstinence decreased subsequent nicotine-seeking in both males and females [57], [58]. Interestingly, in females, but not males, levels of nicotine-seeking were also decreased under a locked wheel control condition as compared to a no-wheel condition indicating that the presence of the wheel in the environment (i.e., as an enrichment) was sufficient to reduce nicotine-seeking in females [58]. These findings parallel results reported in a community intervention study showing that while boys showed a reduction in smoking behavior when the enrichment program had an exercise component, girls benefitted from programs with and without an exercise component [24], [71]. These findings suggest that exercise or non-exercise environmental enrichment may be effective early interventions for reducing nicotine use and addiction in females.

The purpose of this study was to determine in an adolescent-onset female rat model of nicotine addiction whether the efficacy of exercise as an intervention differs from non-exercise environmental enrichment. A saccharin-sweetened solution (0.25%) was selected for non-exercise enrichment because it is a highly palatable, non-caloric reward that, unlike a running wheel (locked or unlocked), does not induce exercise or play behavior [34], [58]. As with the exercise intervention, rats assigned to the saccharin intervention were given 2-hr/day access to the saccharin solution throughout the 10-day abstinence period. Additional control rats were housed in polycarbonate cages without access to running wheels or saccharin. As in our previous studies, we used extended access (23-hr/day) self-administration conditions that result in levels of nicotine intake that are comparable to those observed in humans [69], and that induce significant extinction and cue-induced reinstatement responding following abstinence [1], [57], [58].

The efficacy of exercise versus saccharin during abstinence was examined as a function of estrous cycle phase given findings indicating that hormonal status influences both relapse vulnerability and treatment outcome in females (e.g., [56]; for review see [72]). For example, numerous preclinical studies have shown that levels of motivation for nicotine ([38]; but see [13]), and other stimulants such as cocaine vary across the estrous cycle ([33]; Lynch et al. [37]; [54]), with highest levels reported during estrus, a period associated with a higher ratio of estradiol to progesterone [16]. Although few studies have included a large enough sample size to examine estrous cycle phase differences in levels of nicotine-seeking (~ 3–7/group; [17]), previous research with other stimulants has shown that levels of drug-seeking are also highest in females tested during estrus as compared to non-estrus phases [16], [31], [32], [51]. Importantly, levels of nicotine craving are cyclically regulated in women [3], [19], and like findings in rats, in women, they are highest when the ratio of estradiol to progesterone is high (i.e., during the follicular phase; [72]).

Based on previous findings showing that environmental enrichment, including access to sweet rewards, reduces relapse vulnerability for other drugs of abuse [62], as well as findings showing that girls benefitted from both exercise and non-exercise based environmental interventions [24], we predicted that exercise or saccharin during abstinence would decrease subsequent nicotine-seeking. Furthermore, based on our previous findings in females showing that access to a locked wheel was equally effective at reducing drug-seeking as running in an unlocked wheel [51], [58], we predicted that saccharin would produce a similar decrease in nicotine-seeking as compared to exercise. Finally, based on findings indicating that hormonal status influences relapse vulnerability and treatment outcome in women [4], [39], [72], we hypothesized that levels of nicotine-seeking would be highest during estrus as compared to non-estrus phases, and that the efficacy of exercise versus saccharin during abstinence would vary between females tested during estrous versus non-estrous phases.

Section snippets

Animals

Adolescent female Sprague-Dawley rats (N = 63) arrived on postnatal day (PND) 22 from Charles River Laboratories (Portage, ME, USA). Females were selected for two reasons.

First, females are under-represented in preclinical studies, and there have been recent requests to increase their use in research relevant to human health [11]. This is particularly true for preclinical studies on nicotine addiction where very few studies have included females, and even fewer have examined estrous cycle effects

Data analysis

All data presented are mean ± standard error of mean (SEM). Group differences were analyzed with repeated measures analysis of variance (ANOVA). Between group factors included intervention during abstinence (exercise, saccharin, control) and estrous cycle phase (estrus, non-estrus), and dependent measures included responding and intake during the 10 extended access self-administration sessions, daily distance run during abstinence, daily saccharin intake and preference (defined as saccharin

Extended access nicotine self-administration

Before abstinence and the subsequent exercise, saccharin, or control interventions, each of the groups showed a similar pattern of responding over the 10-day period of extended access self-administration (Fig. 2A). Females that were subsequently tested on nicotine-seeking during estrus versus non-estrus phases within each of these groups also didn't differ on levels of responding for nicotine (Fig. 2B) or levels of nicotine intake (average mg/kg/day ± SEM; exercise, estrus: 1.3 ± 0.1, non-estrous:

Discussion

The goals of this study were to determine whether the efficacy of exercise at reducing nicotine-seeking differed from non-exercise based environmental enrichment (saccharin), and to determine whether the efficacy of these interventions varied between females tested during estrus versus non-estrus phases. Consistent with our hypotheses, we found that levels of nicotine-seeking were highest during estrus, and that exercise or saccharin during abstinence decreased subsequent nicotine-seeking.

Conflict of interest

None.

Funding

This study was supported by the Virginia Foundation for Healthy Youth (grant 8520893; DHB and WJL), and the National Institute on Drug Abuse (grants R01DA024716 and R01DA039093; WJL).

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