Conditioned place preference and self-administration induced by nicotine in adolescent and adult rats

Abstract

Nicotine addiction is a worldwide problem. However, previous studies characterizing the rewarding and reinforcing effects of nicotine in animal models have reported inconsistent findings. It was observed that the addictive effects are variable on different factors (e.g. route, dose, and age). Here, we evaluated the rewarding and reinforcing effects of nicotine in different routes of administration, across a wide dose range, and in different age groups. Two of the most widely used animal models of drug addiction were employed: the conditioned place preference (CPP) and self-administration (SA) tests. Nicotine CPP was evaluated in different routes [intraperitoneal (i.p.) and subcutaneous (s.c.)], doses (0.05 to 1.0 mg/kg) and age [adolescent and adult rats]. Similarly, intravenous nicotine SA was assessed in different doses (0.01 to 0.06 mg/kg/infusion) and age (adolescent and adult rats). In the CPP test, s.c. nicotine produced greater response than i.p. The 0.2 mg/kg dose produced highest CPP response in adolescent, while 0.6 mg/kg in adult rats; which were also confirmed in 7 days pretreated rats. In the SA test, adolescent rats readily self-administer 0.03 mg/kg/infusion of nicotine. Doses that produced nicotine CPP and SA induced blood nicotine levels that corresponded well with human smokers. In conclusion, we have demonstrated that nicotine produces reliable CPP [0.2 mg/kg dose (s.c.)] in adolescents and [0.6 mg/kg dose (s.c.)] in adults, and SA [0.03 mg/kg/infusion] in adolescent rats. Both tests indicate that adolescent rats are more sensitive to the rewarding and reinforcing effects of nicotine.

Keywords: Addiction; Adolescent; Adults; Conditioned place preference; Nicotine; Self-administration.

Fig. 1.

CPP route determination. Effects of subcutaneously (s.c.) or intraperitoneally (i.p.) injected nicotine on the CPP test. (A) Both s.c and i.p. injected nicotine produced CPP at 0.1 and 0.2 mg/kg dose, but only in adolescent rats. Although not significant, the CPP induced by s.c. injected nicotine is somewhat higher than i.p. (B) The locomotor activity during the conditioning phase of CPP. Although not significant, rats injected with s.c. nicotine showed higher distance moved than those injected by i.p. The values are presented means and S.E.M. **p<0.01, ***p<0.001 statistically significant vs. the control group (Dunnet’s posttest).

Fig. 2.

CPP dose determination. (A) Nicotine (s.c.) induced CPP in adolescent and adult rats across a wide dose range. Adolescent rats showed substantially higher CPP relevant to adult rats, particularly at 0.1 and 0.2 mg/kg nicotine. Adult rats also showed CPP at 0.6 mg/kg dose. (B) As confirmation, nicotine pretreated rats (0.5 mg/kg s.c., 7 days, 2 times a day) adolescent rats still showed higher nicotine CPP score at 0.2 mg/kg while pretreated adult rats at 0.6 mg/kg. The values are presented as means and S.E.M. *p<0.05, **p<0.01, ***p<0.001 statistically significant vs. the control group (Dunnet’s posttest).

Fig. 3.

Self-administration data. Nicotine self-administration in adolescent and adult rats. (A) The number of lever responses made or (B) infusions obtained by adolescent and adult rats during the 2 h/day, 10-days nicotine SA sessions under the FR1, FR2, and FR3 schedules. Filled symbols indicate lever responses on the active lever while unfilled symbols show responses for the inactive lever. The values are presented means and S.E.M. *p<0.05, **p<0.01, ***p<0.001 statistically significant vs. the control group (Bonferroni’s posttest).

Fig. 4.

Blood nicotine level. Blood nicotine levels induced by dosages that produced nicotine CPP and SA. Blood nicotine levels in adolescent rats after single subcutaneous injection of 0.2 mg/kg of nicotine (CPP) or immediately after a 0.03 mg/kg/infusion nicotine SA session (mean of 10 infusions).