Sex differences in conditioned nicotine reward are age-specific
Introduction
Cigarette smoking is the leading cause of preventable death in the United States and approximately 20% of American adults are current cigarette smokers, with males (23%) having a slightly higher rate than females (18%) (CDC, 2010). The rate of cigarette smoking in high school students in the United States is only slightly less (17%) than that of American adults, with boys having a slightly higher rate than girls (20% vs. 15%, respectively) (NSDUH, 2010). These statistics are concerning because it is well known that approximately 80% people who start smoking before the age of 18 go on to become regular smokers as adults (CDC, 2003). In fact, children and adolescents may be especially susceptible to nicotine addiction as symptoms of dependence can emerge as early as the first time or first few times tobacco is used (DiFranza et al., 2000) and can even develop in adolescents not classified as daily smokers (i.e., weekly or monthly smokers) (Panday et al., 2007).
Although more males than females smoke cigarettes in both age groups, there is some evidence that female cigarette smokers may be more susceptible to the negative health consequences of tobacco use. For example, females metabolize nicotine faster (and, thus, must dose themselves accordingly), may be more likely to develop chronic obstructive pulmonary disorder (COPD), and have more difficulty with tobacco cessation (reviewed in Rahmanian et al., 2011) than male cigarette smokers. Further, nicotine craving may be more severe in adolescent females than in adolescent males (Panday et al., 2007). Therefore, it is important to understand sex and age differences in behaviors related to nicotine and tobacco, as well as nicotine reward.
Preclinical animal models are useful to examine whether biological sex differences and age differences have considerable effects on behaviors related to nicotine use and dependence (Carroll and Anker, 2010, Carroll et al., 2009, Lynch et al., 2002, O'Dell and Khroyan, 2009). During adolescence, subjects exhibit a unique pattern of behavioral and neurochemical responses to nicotine that are different in males and females. Examples of these age- and sex-specific behaviors and responses are described below.
Female adult rats acquire nicotine self-administration faster than males at the lowest training doses (Chaudhri et al., 2005, Donny et al., 2000, Lanza et al., 2004), and self-administer more intravenous infusions of nicotine per session than males (Rezvani et al., 2008). Although these sex differences seem to be diminished at the end of acquisition and during maintenance (Chaudhri et al., 2005, Donny et al., 2000, Lanza et al., 2004), females are more motivated to initially obtain nicotine as compared to males (Donny et al., 2000). If these findings extrapolate to humans, then perhaps women are more sensitive to lower doses of nicotine, and are more likely to continue tobacco use after fewer “tries” than are men. In adolescence, males administer more nicotine than during adulthood, after which rates decline to adult rates (Levin et al., 2007). In females, adolescents also administer more nicotine than adults; however, this difference is maintained into adulthood (Levin et al., 2003). Thus, starting nicotine during adolescence leads to different use patterns in adults compared to initiating administration in adulthood, and this is sex-dependent.
As sex differences in nicotine self-administration occur in adults, there also are sex differences in behavioral actions of nicotine in adolescents. Data from our laboratory have shown that adolescent females rapidly become sensitized to the locomotor-activating effects of nicotine, with significant effects seen on day 2 of treatment (Collins and Izenwasser, 2004). This finding is in contrast to adult female and male rats that exhibited significant sensitization beginning on day 5 of treatment. Further, adolescent male rats did not become sensitized to the locomotor-activating effects of nicotine within a 7-day treatment period, a finding that has been shown in our laboratory (Collins and Izenwasser, 2004, Collins et al., 2004a) and others (Schochet et al., 2004). Although the adolescent male and female rats were tested during the periadolescent period (postnatal days 28–40; Spear and Brake, 1983) in these studies, males and females have different rates of maturation (Ojeda et al., 1980, Ojeda et al., 1983) that could contribute to sex differences in nicotine self-administration and sensitization during adolescence. Similar to adults, adolescent female rats more easily acquire nicotine self-administration and express greater motivation to earn nicotine than adolescent male rats (Lynch, 2009).
In previous research, it has been shown that a moderate dose of nicotine (i.e., 0.6 mg/kg) produces CPP in adolescent rats but not adult rats when male and female data were combined (Vastola et al., 2002). However, the dose used in this study was based on the weight of the salt rather than nicotine as a free base, so the amount of nicotine actually received by these animals was somewhat lower. Others found similar results, in which adolescents developed CPP to the highest tested doses (0.5–0.8 mg/kg nicotine base), but older adolescents and adults did not (Belluzzi et al., 2004, Brielmaier et al., 2008, Shram et al., 2006). Torres et al. (2008) described the same results as mentioned above, but also found that both adolescents and adults developed CPP to 0.2 mg/kg nicotine. These results were specific to males, as females were not tested. In females, adolescents developed maximal CPP to 0.6 mg/kg, whereas adults developed CPP to 1.2 mg/kg nicotine (Torres et al., 2009).
Sex differences in nicotine CPP have been examined in adult animals by several groups. It has been reported that adult male rats developed CPP in response to 0.1 and 0.2 mg/kg nicotine base (but not any higher doses), whereas adult females did not develop CPP to any of the doses tested (0.1–0.6 mg/kg base) (Yararbas et al., 2010). Results reported by Torres et al. (2009) were similar, in which male rats had maximal CPP to 0.2 mg/kg nicotine and females had maximal CPP to 1.2 mg/kg nicotine; males and females developed conditioned place aversion to 1.8 mg/kg. However, Wistar rats were used in the study by Torres, whereas Sprague–Dawley rats were used in the study by Yararbas. Comparisons between the two studies are somewhat limited because of potential strain differences. Further, sex differences in nicotine CPP are not species-dependent; as male and female differences also have been reported in mice. For example, both male and female mice developed significant CPP to 0.32 mg/kg nicotine, but CPP was greater in females than males at this dose (Isiegas et al., 2009). These results give credence to the idea that sex differences in nicotine reward are not specific to rats and that this likely is a general phenomenon. However, the current literature lacks reports in which effects of age and sex on nicotine reward have been addressed by directly comparing male and female adults and adolescents using nicotine conditioned place preference.
In light of this previous literature, it is clear that the rewarding effects of nicotine are different in male and female rats and that these differential responses likely will be age-specific. While males and females and adolescents and adults have been studied, full dose–response curves for nicotine CPP in all four groups have not yet been reported in a single study. In the present study, the rewarding effects of nicotine were measured using CPP to several doses of nicotine, such that full dose–response curves were attained in male and female adult and adolescent rats. In addition, the responsiveness of brain nicotinic acetylcholine receptors (nAChRs) to stimulation by nicotine was measured in each group to explore possible neurobiological correlates underlying any age and sex differences.
Section snippets
Subjects
Naïve periadolescent male (n = 110), periadolescent female (n = 52), adult male (n = 72), and adult female (n = 68) Sprague–Dawley rats were used (Charles River, Wilmington, MA). All rats were housed in a light- (12 h light/dark cycle with lights on at 7 a.m. and off at 7 p.m.), temperature- (21 ± 2 ºC) and humidity-controlled vivarium (53 ± 13%). At the start of the experiment, male and female periadolescent rats (postnatal day (PND) 34) weighed an average of 126.1 ± 1.9 g and 117.3 ± 1.5 g respectively, and the
Nicotine-induced conditioned place preference
In periadolescent male rats (PAM), 3 days of conditioning induced a significant conditioned place preference (CPP) to low doses of nicotine. Specifically, the 0.05 [t(11) = 3.989, p ≤ 0.002], 0.1 [t(11) = 3.352, p ≤ 0.001], and 0.2 [t(13) = 3.967, p ≤ 0.002] mg/kg nicotine doses induced significant place preference in the PAM group whereas the higher doses of nicotine (0.4, 0.6, 0.8 and 1.0 mg/kg) and the lowest dose of nicotine (0.01 mg/kg) did not (Fig. 1A). In contrast, moderate doses of nicotine such as
Discussion
The purpose of these studies was to examine effects of sex and age on conditioned place preference (CPP) to multiple doses of nicotine and on the density of nicotinic acetylcholine receptors (nAChR) in the caudate putamen and nucleus accumbens of adolescent and adult male and female rats. The present data show that adolescent and adult males (PAM and ADM, respectively) develop place preferences to lower doses of nicotine than age-matched females. Further, there were age-specific responses
Acknowledgments
The animals used in this study were maintained and the studies were conducted in accordance with the guidelines of the Guide for Care and Use of Laboratory Animals, National Research Council, Department of Health, Education and Welfare, NIH Publication 85-23, revised 1985. This work was supported by the National Institute on Drug Abuse and the NIH Office of Research on Women's Health (grant DA 024584-0002).
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