Adolescent nicotine and tobacco smoke exposure enhances nicotine self-administration in female rats

Abstract

Most people start experimenting with tobacco products or e-cigarettes in early adolescence and become habitual smokers in late adolescence or adulthood. These studies investigated if exposure to tobacco smoke or nicotine during early and mid-adolescence affects nicotine intake in late adolescence and early adulthood. Male and female rats were exposed to tobacco smoke from low- and high-nicotine SPECTRUM cigarettes or nicotine (0.3 mg/kg, twice a day) from postnatal day (P) 24-42. The self-administration sessions started at P55. The rats self-administered nicotine for 14-15 days under a fixed-ratio 1 schedule, and on the first day, the maximum number of infusions was twenty. Exposure to smoke from high, but not low, nicotine cigarettes during adolescence increased nicotine self-administration in female but not male rats. Adolescent treatment with nicotine facilitated nicotine self-administration. On the first day of nicotine self-administration, nicotine-treated rats reached the maximum number of infusions before the saline-treated control rats. Nicotine intake was also higher in the nicotine-treated female rats than in the saline-treated females. There was no sex difference in nicotine intake in controls when the data from the studies were combined. Smoke exposure led to a dose-dependent increase in plasma nicotine and cotinine levels in adolescent rats. Exposure to smoke from high-nicotine cigarettes and 0.3 mg/kg of nicotine led to plasma nicotine and cotinine levels that are similar to those in tobacco users. These findings indicate that in females, but not males, exposure to nicotine during adolescence may facilitate smoking and e-cigarette use later in life.

Keywords: Adolescent; Nicotine; Rats; Self-administration; Sex differences; Tobacco smoke.

Figure 1.. Body weights of adolescent male and female rats exposed to tobacco smoke or nicotine.

The figures depict the absolute body weights of the rats exposed to tobacco smoke (A) and nicotine (C) and the body weights expressed as a percentage of the baseline values (B, D). The adolescent male and female rats were exposed to tobacco smoke or nicotine from P24–42. Weight gain was slightly reduced in the female rats exposed to smoke with a low level of nicotine, but this effect was not observed when the body weights were expressed as a percentage of the baseline values. Asterisks indicate lower body weight compared to the females exposed to air. N = 8–11/group. Data are expressed as means ± SEM. ** P < .01. Abbreviations: BW, body weight; low, smoke with low level of nicotine; high, smoke with high level of nicotine.

Figure 2.. Adolescent exposure to tobacco smoke with a high level of nicotine increases nicotine self-administration in female rats.

The rats were exposed to tobacco smoke with low (A, B) or high levels (C, D) of nicotine during early and mid-adolescence and nicotine self-administration started during late adolescence. E) Depicts difference in nicotine intake between the male and female rats exposed to smoke with a high level of nicotine during adolescence. Asterisks indicate significantly different from the male HNS rats and plus signs from the female air rats. The rats had access to nicotine 5 days per week and total nicotine intake and responding on the inactive lever were recorded. Abbreviations: LNS, low nicotine smoke; HNS, high nicotine smoke; LL, left lever. N = 8–11/group. Bonferroni post-hoc test: +,* P < .05, ** P < .01. Data are expressed as means ± SEM.

Figure 3.. Adolescent nicotine-treatment increases nicotine self-administration in female rats.

Rats treated with nicotine during early and mid-adolescence reached the maximum number of infusion (20) before rats treated with saline. The effect of nicotine pre-treatment on the speed of nicotine intake was most pronounced in the females (A). The rats had access to nicotine 5 days per week and total nicotine intake (B) and responding on the inactive lever (C) were recorded. Asterisks indicate a significant difference compared to the female-saline rats. Bonferroni post-hoc test: ** P < .01. N = 9–10/group. Abbreviations: LL, left lever. Data are expressed as means ± SEM.

Figure 4.. Similar levels of nicotine intake in male and female rats.

The self-administration data of the saline and air-control groups of the first 2 experiments were combined and it was determined if there was a sex difference in nicotine intake in late adolescent rats. The males and females self-administer the same amount of nicotine when they have access to a standard dose of nicotine, 0.03 mg/kg/inf under an FR1 schedule of reinforcement. N=18–19/group. Data are expressed as means ± SEM.

Figure 5.. Nicotine and cotinine levels in rats after exposure to tobacco smoke or nicotine.

Adolescent male and female rats were exposed to tobacco smoke from low- or high-nicotine cigarettes for 1 h and samples were collected immediately after smoke exposure. Adolescent rats were also exposed to a low (0.1 mg/kg), intermediate (0.3 mg/kg), and high dose of nicotine (0.6 mg/kg) and blood samples were collected 15 min later. Asterisks indicate a higher level of nicotine or cotinine compared to rats exposed to tobacco smoke with a low level of nicotine. Dollar signs indicate a higher level of nicotine or cotinine compare to rats of the same sex treated with 0.1 mg/kg of nicotine. Plus signs indicate higher levels of nicotine compared to rats of the same sex treated with 0.3 mg/kg of nicotine. Bonferroni post-hoc test: * P < 0.05, **, $ $ P < 0.01, ***, +++, $ $ $ P < 0.001.. N=5–10/group. Abbreviations: NIC, nicotine. Data are expressed as means ± SEM.