Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats

Abstract

Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts early during adolescence. These observations suggest that adolescence could be a "critical" ontogenetic period, during which drugs of abuse have distinct effects responsible for the development of dependence later in life. We compared the long-term behavioral and molecular effects of repeated nicotine treatment during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not a similar exposure in the postadolescent period, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period, characterized by enhanced neurobehavioral vulnerability to nicotine.

Figure 1.

Animals pre-exposed to nicotine during periadolescence (right panel) and postadolescence (left panel) differed during acquisition of nicotine SA (age × treatment × day interaction, F_(14,350) = 1.80; p < 0.05). Within the periadolescent group, nicotine-pretreated animals showed more nose pokes in the active device delivering nicotine (0.04 mg/kg per infusion) than did vehicle-pretreated controls, and this during the entire acquisition period (treatment effect, F_(1,11) = 4.64; p < 0.05). Conversely, within the postadolescent group, nicotine-pretreated animals showed more active nose pokes than vehicle-pretreated controls, only during the FR1 period (treatment × day × hole interaction, F_(14,196) = 2.03; p < 0.05). The two groups did not differ anymore when the FR requirement was increased over days. The two vehicle-pretreated groups did not differ at any time (age effect, F_(1,12) = 2.28; p = 0.6). Responses in the inactive device had no schedule consequences and were used as a control of SA. The two age groups (periadolescent and postadolescent) did not differ for the number of inactive responses. Similarly, in both age groups, vehicle-treated and nicotine-pretreated animals did not differ for inactive responses. FR indicates the number of active responses necessary to obtain one infusion of nicotine. *p < 0.05 in comparison with corresponding vehicle-pretreated animals.

Figure 2.

Animals pre-exposed to nicotine during periadolescence and postadolescence differed during a between session PR schedule for nicotine SA. FR indicates the number of responses necessary to obtain one infusion of nicotine. Because animals pretreated with vehicle during either periadolescence or postadolescence did not differ (F_(1,12) = 2.28; p > 0.60), they were collapsed in the vehicle group. In the postadolescent group, the number of responses in the active device delivering nicotine (0.04 mg/kg per infusion) did not differ between animals pretreated with nicotine and animals pretreated with vehicle, with the exception of FR1 (Fig.1). In these two groups, responses increased regularly up to FR10 and progressively decreased at FR20, 25, and 30, providing the typical bell-shaped curve observed with this PR schedule. In animals pretreated with nicotine during periadolescence, no significant decrease in response was observed up to FR30, these animals showing a higher number of active responses than the other two groups at FR20, 25, and 30(p < 0.05).

Figure 3.

Animals pre-exposed to nicotine during periadolescence and postadolescence differed for transcript levels of different subunits of the nAChRs in the ventral midbrain. Results are expressed as fold changes from the matched vehicle-pretreated controls. An upregulation of the α5, α6, and β2 subunits was found in animals pretreated with nicotine during periadolescence. In contrast, no significant changes were found in animals that received the same nicotine pretreatment but during postadolescence, with the exception of the β3 subunit that was similarly increased in both groups. **p < 0.001 in comparison with animals pretreated during postadolescence.