Animal and human studies will be conducted in parallel to determine the threshold dosing for the first symptoms of nicotine dependence in adolescent humans and for the first neurochemical changes brought on by nicotine in the brains of adolescent rats. Separate experiments will evaluate the upregulation of high affinity nicotinic cholinergic receptors in the midbrain reward centers, and the activation of cholinergic reward pathways. These experiments will be conducted to explore the effects of low-dose intermittent exposure to nicotine, simulating the nicotine exposures commonly present at the onset of nicotine dependence in teenagers. A comparison will be made regarding the sensitivity of adolescent and adult rats to the neurochemical effects of nicotine that are thought to be responsible for dependence. Intermittent and continuous dosing will be compared and gender differences will be explored. Adolescents and adults will be compared in the speed with which neurochemical changes occur. In humans, a prospective longitudinal study employing 1200 subjects and individual interviews will be conducted to explore individual differences in the speed with which nicotine dependence develops. The nicotine dosing and pattern of use at the onset of the first symptoms and full dependence will be studied. Investigations will explore why some youths develop symptoms of dependence upon exposure to nicotine while others do not. A new theory-based measure of early dependence for youths will be tested against established measures of dependence.
