Nicotine's Effects on the Developing Adolescent Limbic System

Adolescence is a critical time in limbic development that also coincides with the onset of tobacco use. Epidemiological data show that teen smokers are more likely to use other types of drugs later in life, suggesting that tobacco induces long-term alterations in motivational circuitry. Previous studies done by our laboratory have shown that adolescent rats pretreated for 4 days with a low-dose of nicotine (60 microg/kg/day), the psychoactive component of tobacco, show enhanced acquisition of cocaine, methamphetamine, and alcohol self-administration, an effect not observed in adults. This supports the hypothesis that nicotine alters the adolescent reward system.;Using a reinstatement model of self-administration, which models human relapse, I found long-lasting changes in reward-seeking behavior induced by brief, low-dose adolescent nicotine exposure. Adolescent nicotine pretreatment enhanced both acquisition and extinction of cocaine-seeking behavior but did not affect reinstatement of cocaine-seeking behavior. These changes were not seen in adults.;Since drug-seeking behavior is reliant on dopamine signaling in limbic regions that mediate reward, I used specific dopamine receptor antagonists to investigate the effects of nicotine pretreatment on dopamine 2 receptor (D2R), D3R, and D4R signaling in adolescent rats. Using locomotor activity and penile response as measures of dopamine function, I found that adolescent nicotine pretreatment enhanced quinpirole-induced locomotion via D2Rs and penile response via D3Rs. Nicotine also enhanced expression of the immediate early gene, c-fos, in hypothalamic corticotropin releasing factor (CRF) neurons in adolescents but not adults, and CRF mediated nicotine enhancement of adolescent penile response.;Nicotine pretreatment during adolescence enhanced quinpirole- induced c-fos mRNA expression, a marker of recent neuronal activation, in brain regions that participate in networks important for mediating motivated behavior. Evaluation of network-level coordinated c-fos mRNA expression revealed that adolescent nicotine pretreatment significantly changed functional activity of networks involved in mediating motivated behavior and spatial recognition. The predictive validity of this novel method of assessing network activity was confirmed with a behavioral test that showed adolescent nicotine treatment to enhance spatial recognition. Thus, nicotine alteration of developing adolescent limbic circuits important for mediating motivated behavior may result in long-term changes in limbic function.