Unique Effects of Brief Nicotine Exposure on the Adolescent Brain

Clinical studies have shown that adolescent smoking is associated with a variety of health risk behaviors including the development of anxiety disorders, high-risk sexual behavior and illicit drug use. Nicotine, the main psychoactive component in tobacco, can alter critical aspects of brain maturation during these periods by interfering with nicotinic acetylcholine receptor control of central reward pathway development. Neurotransmitter systems implicated in the modulation of these behaviors are not fully mature during this period, and can be critically altered by external stimuli, such as smoking.;In the present dissertation, I investigated the effects of a brief nicotine exposure on the sensitivity of brain reward systems. Using the rat as an animal model, I have found that four-day pretreatment with a low dose of nicotine (60mug/kg; i.v.), equivalent to that found in 1-2 cigarettes, has unique behavioral effects in adolescence. These changes in behavior may be attributed to neuronal activation in the nucleus accumbens-shell and basolateral amygdala, two brain regions that regulate drug seeking and motivated behavior. Neurochemical analyses suggest that forebrain limbic systems continue to mature in adolescence, and that adolescent nicotine exposure caused significant alterations in the presynaptic maturation of the serotonin (5-HT) system.;Early adolescent nicotine exposure also induced alterations in functional response to direct DA agonists, including enhanced locomotion and proerectile activity of the D2-like agonist, quinpirole. These changes were unique to the early adolescent period and long lasting. Pharmacological inhibition of the 5-HT1A receptor (5-HT1A-R) blocked nicotine-induced enhancement of locomotion, while direct activation of the 5-HT1A-R emulated nicotine's effects. However, erectile response was not affected by 5-HT1A-R manipulation, suggesting an additional pathway for nicotine-induced changes in adolescent brain.;Neurochemical studies and in situ hybridization analysis showed unique, nicotine-induced alterations in adolescent limbic, sex and stress-related systems, and novel patterns of network interaction. My results demonstrate that nicotine exposure during early adolescence directly interferes with development of DA and 5-HT systems, with important consequences for mental-health related behaviors.