Low-dose nicotine self-administration is reduced in adult male rats naïve to high doses of nicotine: implications for nicotine product standards.

Tobacco control policies should aim to decrease the number of people who become smokers and better enable current smokers to quit smoking. Smoking initiation rates are still high, with one in four U.S. high school seniors smoking daily (US Department of Health and Human Services, 2012). Additionally, two thirds of current smokers express that they would like to quit smoking, but only 6.2% of smokers actually quit each year (CDC, 2011). In 2009, Congress passed the Family Smoking Prevention and Tobacco Control Act which permits the regulation of tobacco products and their constituents, including the reduction, but not elimination, of the nicotine content in cigarettes (US Congress, 2009). A policy that reduces the nicotine content of a cigarette below a threshold for addiction could substantially decrease initiation and increase smoking cessation (Benowitz and Henningfield, 1994), but such a policy requires an understanding of the dose range that supports initiation as well as maintenance of smoking behavior. Importantly, a history of smoking may shift the dose-response curve for the primary reinforcing effects of nicotine to the left (sensitization) or to the right (tolerance). In this case, a nicotine reduction policy may impact individuals who start smoking reduced nicotine content cigarettes (i.e., new smokers) differently from those who were smoking prior to policy implementation (i.e., current smokers). If a history of smoking normal nicotine content cigarettes increases sensitivity to low doses of nicotine, ongoing research on reduced nicotine cigarettes that uses current smokers as participants might underestimate the public health impact of regulation on individuals who try smoking for the first time after regulation. Understanding the impact of prior nicotine and tobacco use is critical in determining the likely effects of a reduction in nicotine content on smoking behavior. Non-human research is valuable for studying how a nicotine reduction policy would differentially affect new and experienced cigarette smokers because ethical issues make experimentally manipulating the initiation of smoking impossible. Nicotine self-administration research, in which animals respond for intravenous (i.v.) infusions of nicotine, is likely to be particularly informative. Two dose-response curves, each plotting the rate of self-administration across low nicotine doses, can be compared: one for acquisition in which rats are first given the opportunity to respond for low doses of nicotine (analog for “new smokers”), and one following reduction after rats have a history of responding for a higher dose of nicotine (analog for “current smokers”). While the exact doses used are unlikely to translate to humans, the relation between the two dose-response curves may provide important information about the functional effects of a history of self-administering a higher dose of nicotine. To date, the relationship between acquisition and reduction dose-response curves is unknown. While there are studies investigating self-administration across doses of acquisition (Chen, Matta, & Sharp, 2007; Cox, Goldstein, & Nelson, 1984; Donny et al., 1998; Sorge & Clarke, 2009) and reduction (Grebenstein, Burroughs, Zhang, & LeSage, 2013; Smith, Levin, Schassburger, Buffalari, Sved, & Donny, 2013), it is difficult to compare the results of these studies to previous studies investigating the acquisition dose-response curve because of methodological differences including strain of rat, nicotine-paired environmental stimuli, schedule of reinforcement, and daily duration of access (Donny et al., 2012). Research has shown that exposure to nicotine alters subsequent self-administration (Adriani et al., 2003; Shoaib, Schindler, & Goldberg, 1997), and in one small study, Cox et al. (1984), demonstrated a nicotine-dose reduction to 3 μg/kg/infusion produced an increase in behavior compared to the pre-reduction baseline of 30 μg/kg/infusion, even though 3 μg/kg/infusion failed to produce acquisition in a separate group of rats. If replicated, these data indicate that individuals with a history of smoking cigarettes with higher nicotine contents may smoke low-nicotine cigarettes at a higher rate than individuals who initiate smoking with low-nicotine cigarettes. The present experiment directly compared the dose-response curve for acquisition to the one for reduction, using both a between-subjects and a within-subjects approach. For the between-subjects comparison, a large group of rats acquired nicotine self-administration at a high nicotine dose (60 μg/kg/infusion) before experiencing a reduction to one of three low doses of nicotine (3.75, 7.5, or 15 μg/kg/infusion) or vehicle alone. The self-administration behavior of these rats at the low doses of nicotine may be thought of as an analog for current smokers who experience a large reduction in the nicotine content of their cigarettes. Their self-administration behavior at the low doses was compared to a group of rats who were given the opportunity to acquire nicotine self-administration for the first time at one of the same low doses or vehicle alone. The self-administration behavior of these rats may be thought of as an analog for new smokers who begin smoking after the nicotine content in cigarettes has been reduced. Second, we examined the effects of a history of high nicotine dose self-administration using a within-subjects comparison of self-administration behavior before and after experience self-administering a high dose of nicotine. Techniques were employed to more appropriately model a policy scenario in which the nicotine content of cigarettes is greatly reduced. A light stimulus was paired with nicotine infusions to model the experience of smoker who experiences environmental cues paired with their smoking. Additionally, a cocktail of non-nicotine cigarette smoke constituents was included along with nicotine infusions to better model the experience of a smoker. Some of these constituents have been shown to have behavioral effects on their own or in combination with nicotine (Bardo, Green, Crooks, & Dwoskin, 1999; Belluzzi, Wang, & Leslie, 2005; Clemens, Caille, Stinus, & Cador, 2009; Guillem et al., 2005; Hoffman & Evans, 2013; Villegier, Lotfipour, McQuown, Belluzzi, & Leslie, 2007). Although these manipulations make it difficult to isolate the mechanism(s) responsible for a shift in self-administration, they have the advantage of being more directly relevant to the critical regulatory questions faced by the FDA that cannot be easily addressed in clinical samples (Donny et al., 2012).