Variability in initial nicotine sensitivity due to sex, history of other drug use, and parental smoking

Abstract

Initial sensitivity to nicotine's effects during early exposure to tobacco may relate to dependence vulnerability. We examined the association of initial nicotine sensitivity with individual difference factors of sex, other drug use history (i.e. cross-tolerance or cross-sensitization), and parental smoking status in young adult nonsmokers (N = 131). Participants engaged in 4 sessions, the first 3 to assess the dose–response effects of nasal spray nicotine (0, 5, 10 μg/kg) on rewarding, mood, physiological, sensory processing, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Men had greater initial sensitivity than women to some self-reported effects of nicotine related to reward and incentive salience and to impairment in sensory processing, but men and women did not differ on most other effects. Prior marijuana use was associated with greater nicotine reward, nicotine reinforcement was greater in men versus women among those with prior marijuana use, and having parents who smoked was related to increased incentive salience. However, history of other drug use and parental smoking were not otherwise associated with initial nicotine sensitivity. These findings warrant replication with other methods of nicotine administration, especially cigarette smoking, and in more diverse samples of subjects naïve to nicotine. Yet, they suggest that sex differences in initial sensitivity to nicotine reward occur before the onset of dependence. They also suggest that parental smoking may not increase risk of nicotine dependence in offspring by altering initial nicotine sensitivity, and that cross-tolerance between other drugs and nicotine may not be robust in humans.

Introduction

Individual differences in sensitivity to nicotine upon initial exposure may be important in understanding variability in the risk of becoming nicotine dependent. The “sensitivity” model of Pomerleau (1995) proposes that individuals at higher risk for nicotine dependence experience greater positive, and perhaps aversive, effects of nicotine when they first experiment with smoking, compared to individuals at lower risk for dependence. Greater effects with early exposure may increase the chances of repeated tobacco use, leading to escalation of smoking and onset of dependence. In several studies, adults who currently smoke retrospectively reported having had greater pleasant sensations the first time they ever smoked, compared to adults who had never smoked regularly but had had some exposure (e.g., Hu et al., 2006, O’Connor et al., 2005, Pomerleau et al., 2004). The sensitivity model is based on animal research showing genetic or other individual differences in sensitivity to nicotine effects (Le et al., 2006, Marks et al., 1991, Schechter et al., 1995). Some mouse strains that are more sensitive than others to nicotine upon initial exposure may show greater subsequent nicotine preference in conditioned place preference testing (Schechter et al., 1995).

Based on this notion, it would be important to identify specific factors that account for the variability in initial nicotine sensitivity in humans. Such factors could increase our understanding of the etiology of dependence, as well as provide directions for subpopulations of youth in need of greater efforts at prevention of tobacco use. One important individual difference may be due to sex (i.e. gender). On measures of reward and reinforcement, women may be less responsive than men to manipulations of nicotine exposure, while women may be more responsive than men to manipulations of non-nicotine components of cigarette smoking, such as cues (Perkins, 1996, Perkins, in press; Perkins et al., 1999, Perkins et al., 2001a). However, because virtually all of this research has been conducted with dependent smokers, it is not clear whether the sex difference in sensitivity to nicotine results from chronic exposure over years of regular smoking or may be present from the start of experimentation with smoking in teens. Two studies of nonsmokers examined sex differences in nicotine self-administration via nasal spray using a choice procedure (i.e. reinforcement) and found significantly less choice in women versus men when 2.5 μg/kg/spray was the dose (Perkins et al., 1997), but not when 1.5 μg/kg/spray was the dose (Perkins et al., 2001b). Very little other research has explicitly examined sex differences in initial sensitivity to nicotine, i.e. nicotine sensitivity among naïve individuals.

Among other potential individual differences in initial sensitivity to nicotine, chronic use of some drugs can decrease or increase sensitivity to not only the effects of the same drugs, processes commonly called tolerance and sensitization, respectively, but also to effects of the initial exposure to other drugs, termed cross-tolerance and cross-sensitization, respectively (Kalant, 1996). Alteration in sensitivity to a particular drug may explain why a prior history of other drug use increases subsequent risk of dependence to the first drug (Agrawal et al., 2006). This possibility extends to cigarette smoking, as the risk of subsequent nicotine dependence is increased as a function of greater prior use of other drugs, such as alcohol (e.g., Hoving et al., 2007) and marijuana (Agrawal et al., 2008, Patton et al., 2005; see also Gilpin et al., 2005). Rodent studies demonstrate that prior chronic exposure to caffeine enhances acquisition of nicotine self-administration (Shoaib et al., 1999), suggesting cross-sensitization between caffeine and nicotine reinforcement. Chronic exposure to alcohol may also produce cross-sensitization to some effects of nicotine (Watson and Little, 1999) and cross-tolerance to other effects of nicotine (Luo et al., 1994).

To our knowledge, cross-tolerance or cross-sensitization between prior use of other drugs and nicotine has never been clearly tested, let alone demonstrated, in humans. One study tested the reverse association, cross-tolerance between prior use of nicotine via smoking and sensitivity to another drug, alcohol, and found that self-reported “intoxication” response to acute alcohol intake was attenuated in smokers versus nonsmokers (Madden et al., 1995). However, the influence of prior nicotine exposure on initial sensitivity to alcohol could not be determined from this study since all subjects were regular alcohol drinkers.

Finally, another individual difference factor that may influence initial nicotine sensitivity is parental history of smoking, which is associated with a higher risk of nicotine dependence in offspring (Barman et al., 2004, Bricker et al., 2007, Hu et al., 2006, Jackson et al., 1997, Peterson et al., 2006). For example, some research shows that the number of smoking parents increases risk of smoking escalation in high school, while the number of older siblings who smoke has little effect on escalation after initial exposure to smoking (Bricker et al., 2007). Other research has found that smoking in either parent increases risk of nicotine dependence, although only maternal smoking, and not paternal smoking, is associated with smoking persistence in young adults (Hu et al., 2006).

Among possible explanations for the association between parental smoking and risk of dependence, parental smoking may act as a marker for genetic predisposition to smoke that is transmitted to offspring. Such a predisposition may be reflected in a difference in initial sensitivity to nicotine, which may mediate the risk of dependence. Positive family history of smoking is associated with greater craving responses to either stress or smoking cue imagery, compared to responses of smokers without a family history of smoking (Colamussi et al., 2007). However, this finding does not address sensitivity to nicotine per se and does not address initial sensitivity to early exposure, which requires study of essentially nicotine-naïve individuals. The absence of research on parental smoking and nicotine sensitivity contrasts with extensive research in the alcohol field relating alcohol sensitivity to paternal or family history of alcoholism (Eng et al., 2005, Evans and Levin, 2003, McCaul et al., 1991, Pollock, 1992). In addition, maternal smoking while pregnant exposes the fetus to effects of nicotine and other consequences of smoke inhalation that can alter neural development in ways that later promote dependence in the offspring (Buka et al., 2003).

In sum, greater initial sensitivity to the acute rewarding and reinforcing effects of nicotine may increase risk of nicotine dependence, and factors associated with greater initial sensitivity may identify predictors of vulnerability to dependence. In this study, we examined the influences of subject sex, other drug use, and parental history of smoking on initial sensitivity to acute nicotine administration in young adult nonsmokers. We chose nonsmokers (i.e. those with minimal tobacco exposure history) to ensure that responses to nicotine would reflect their initial sensitivity to the drug, unaltered by the onset of chronic tolerance to nicotine, which occurs fairly rapidly as teens persist in experimenting with cigarettes (Gervais et al., 2006). Tolerance, by definition, blunts overall sensitivity to nicotine and may dampen the degree of variability in sensitivity between individuals (Perkins, 2002, Perkins et al., 2000), thus hampering the identification of factors that explain this variability. To improve the generalizability of our findings, we included young adults with modest prior tobacco exposure because of evidence that two-thirds of those who never become dependent smokers nevertheless have had some tobacco exposure (Anthony et al., 1994).