Sex and ovarian hormones influence vulnerability and motivation for nicotine during adolescence in rats

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Abstract

The purpose of this study was to examine sex differences in sensitivity to nicotine's reinforcing effects during adolescence, a hormone transition phase characterized by rapid and marked changes in levels of gonadal hormones. Male and female rats were trained to self-administer nicotine (5 or 10 µg/kg/infusion) under a fixed-ratio 1 schedule beginning on postnatal day 30. Following acquisition, responding was assessed under a progressive-ratio schedule until postnatal day 45 with blood sampling occurring prior to the first 5 sessions in order to determine the relationship between gonadal hormones (i.e., estradiol and progesterone in females and testosterone in males) and responding for nicotine. Under low dose conditions, a greater percentage of females than males acquired nicotine self-administration. Under progressive-ratio testing conditions, although adolescent females and males initially responded at similar levels, by the end of the adolescent testing period, females responded at higher levels than males to obtain nicotine infusions. Levels of responding under the progressive-ratio schedule were negatively associated with progesterone and positively associated with the ratio of estradiol to progesterone. These findings demonstrate an enhanced sensitivity in adolescent females as compared to adolescent males to nicotine's reinforcing effects with evidence implicating circulating hormone levels as modulating this sensitivity.

Introduction

Men are approximately one and a half times more likely than women to report past month use of a tobacco product and slightly more likely to smoke cigarettes (Substance Abuse and Mental Health Services Administration (SAMHSA), 2007). However, among adolescents, the gender differential is eliminated with adolescent females aged 12 to 17 equal to males on reported rates of current smoking (9.7% versus 10.0%, respectively). Moreover, accumulating evidence indicates that women are more vulnerable on certain aspects of nicotine dependence than are men. For example, compared to male smokers, female smokers take less time to become dependent after initial use, report shorter and less frequent abstinence periods, and have more difficulty quitting smoking (for review see Perkins, 2001).

Results from studies with adult laboratory animals support a greater vulnerability to nicotine self-administration in females compared to males (Chaudhri et al., 2005, Donny et al., 2000, Donny et al., 2004, Rezvani et al., 2008), suggesting that differences observed between men and women smokers have a biological basis. For example, Donny et al. (2000) compared male and female rats on acquisition of nicotine self-administration and found that a greater percentage of females than males acquired self-administration under the low dose conditions. They also showed that females responded at higher levels than males on a progressive-ratio schedule suggesting that they were more motivated to obtain nicotine infusions than were males. Although this study did not find estrous cycle dependent changes in progressive-ratio responding for nicotine, studies conducted with humans suggest that ovarian hormones contribute to smoking behavior in women. For example, phase of the menstrual cycle has been shown to affect the subjective effects of smoking and smoking behavior (DeBon et al., 1995, Mello et al., 1987, Snively et al., 2000; but see Allen et al., 1996, Pomerleau et al., 1994, Marks et al., 1999) and to be predictive of nicotine withdrawal severity (Allen et al., 1999, O'Hara et al., 1989, Perkins et al., 2000) and vulnerability to craving and smoking relapse following abstinence (Pomerleau et al., 2000, Franklin et al., 2004, Franklin et al., 2008, Carpenter et al., 2006, Allen et al., 2008, Allen et al., 2009). Additionally, Sofuoglu et al. (2001) demonstrated that exogenously administered progesterone reduced the positive subjective effects of smoking and craving for cigarettes. Similar findings of an increased vulnerability in females as a function of hormonal phase have been reported in both laboratory animals and humans for a variety of other drugs of abuse (Lynch, 2006, Lynch et al., 2002, Carroll et al., 2004, Becker and Hu, 2008). These findings suggest that ovarian hormones modulate the reinforcing effects of drugs of abuse, including nicotine, raising the possibility that vulnerability to nicotine dependence may vary at hormone transition phases (e.g., adolescence, pregnancy, menopause).

Adolescence is a period of marked hormonal change that is associated with an apparent vulnerability to smoking initiation. Additionally, adolescents, particularly female adolescents, seem to progress more rapidly to nicotine dependence after initial use than adults (SAMHSA, 2007) and show higher rates of dependence, even though adolescents report smoking fewer cigarettes than do adults (Tanski et al., 2004, Storr, 2008). Despite these findings, and the fact that smoking generally begins during adolescence, most animal studies have focused on adult males (but see McQuown et al., 2007, Shram et al., 2008a, Shram et al., 2008b, Levin et al., 2007, Adriani et al., 2003). As a result, very little information is available on sex differences in vulnerability to nicotine dependence during adolescence, and it is not yet known whether changes in vulnerability to nicotine dependence coincide with changes in hormones.

Adolescence in the rat is associated with the onset of puberty and has been broadly defined to include the few days preceding and following its onset (from postnatal day 28 to 42; Spear and Brake, 1983). It is initiated by a surge in gonadal hormones on at around postnatal day 28 (e.g., GnRH, testosterone and estrogen; Corpechot et al., 1981). In adolescent females, vaginal opening occurs on postnatal day 35, and by postnatal day 45, females are randomly cycling (Ojeda et al., 1983). In males, following the surge in gonadal hormone, levels of testosterone continue to increase beginning at around PND 35 with the first free sperm appearing around postnatal day 45 (Ojeda et al., 1980).

An initial study conducted by Klein et al. (2004) in mice showed that oral nicotine consumption in g/kg was significantly greater in adolescent females as compared to adolescent males. Chen et al. (2007) recently showed in rats that adolescent males and females did not differ on acquisition of nicotine self-administration under low dose conditions when responding was assessed beginning during late adolescence (beginning between postnatal days 43 and 45). Levin et al. (2003) also examined nicotine self-administration in female rats during late adolescence (beginning between postnatal days 40 and 46) and showed that adolescent females rapidly acquired self-administration, although a comparison to males was not included. To date, no studies have examined estrous cycle phase in females or gonadal hormone levels in females or males with regard to nicotine self-administration during adolescence. Thus, the goal of this study was to explore sex differences and hormonal influences on acquisition of nicotine self-administration and subsequent motivation for nicotine as assessed under a progressive-ratio schedule in adolescent rats beginning at postnatal day 30 and ending at postnatal day 45. Estrous cycle phase was monitored throughout the study. Blood levels of estradiol and progesterone (females) and testosterone (males) were also examined prior to each of the first 5 progressive-ratio sessions in order to determine the relationship between levels of circulating gonadal hormones and motivation for nicotine. Given previous findings of sex differences in adult rats and previous findings of hormonal influences in humans, we hypothesized that female rats would show an enhanced sensitivity to the reinforcing effects of nicotine as compared to male rats, and that ovarian hormones would underlie the enhanced sensitivity.

Section snippets

Subjects

Female and male Sprague Dawley rats arrived at the laboratory at postnatal day 22 with self-administration testing beginning at postnatal day 30 and continuing until postnatal day 45.

Upon arrival at the laboratory, rats were individually housed in operant conditioning chambers (ENV-018M; Med Associates, St. Albans, VT), and maintained on a 12-hour light/dark cycle (lights on at 7-am) with free access to food and water. In order to ensure that acquisition occurred within the narrow window of

Acquisition

Acquisition of nicotine self-administration was achieved rapidly in both males and females under both dose conditions (Fig. 2). Specifically, under the 5 µg/kg dose condition 5 of 12 males (42%) and 7 of 10 females (70%) met the acquisition criterion within the first 2 sessions. Under the 10 µg/kg dose condition 8 of 14 males (57%) and 6 of 15 females (40%) met the acquisition criterion within the first 2 sessions. Although a similar number of females and males acquired nicotine

Discussion

The goal of this study was to explore sex differences and hormonal influences on acquisition of nicotine self-administration and subsequent motivation for nicotine during adolescence. The results were consistent with our hypotheses that female rats would show an enhanced sensitivity to the reinforcing effects of nicotine and that ovarian hormones would underlie the enhanced sensitivity. Under the low dose condition, a greater percentage of females than males acquired nicotine

Acknowledgements

We would like to thank Florence Breslin for her excellent technical assistance. This work was supported by the Virginia Youth Tobacco Project Small Grants Program and by the University of Virginia. The author has no financial relationships to disclose.

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