CHILDREN AT RISK: HIGH FIELD MRI OF STIMULANT EFFECTS

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DESCRIPTION (provided by applicant): This revised Mentored Research Scientist Development Award (K01) is structured around 3-years of training in proton (1H)- and carbon (13C)-magnetic resonance spectroscopy (MRS), drug abuse research, and exposure to a clinical population of adolescents undergoing treatment for substance abuse disorders. Experimentation with the stimulant nicotine frequently occurs in childhood, and is associated with increased risks for health and illegal substance use. Adolescent nicotine dependence is strongly linked with the experience of one of the following behavioral signs after the first inhaled cigarette: increased relaxation, dizziness, and/or nausea (DiFranza et al., 2004). These behavioral signs are consistent with nicotine's effects on brainstem and cerebellum, particularly regions of the vermis heavily innervated by the vestibular system, called the vestibulocerebellum (VC). This region, enriched in glutamatergic (Glu) neurons, integrates interoceptive sensations from the upper body during conditioning and coordinates the cardiovascular brainstem. Rat cerebellar astrocytes release Glu upon nicotine exposure in vitro. The human VC contains developing astrocytes, which continue growth into early adulthood. PET, MRS and in vitro studies show that cerebellar tissue has high metabolic demands for oxygen, Glu and glutamine (Gin), but low hexokinase activity. Thus, nicotine could developmentally alter cerebellar glia-neuron metabolic relationships. The candidate, by learning to conduct 1H-MRS at 4 Tesla, proposes to study changes in Glu, Gln, and GABA concentrations in the adolescent VC. The research training component will test the hypothesis in nicotine dependent adolescents that Glu concentrations in the VC decline during nicotine withdrawal and increase after a nicotine-gum challenge in 30 (15M/15F) adolescent smokers (14 to 17 years from local area high schools). Metabolite variation in 30 nicotine-free comparison subjects, matched forage, sex, and family history of substance abuse will also be studied. Additional training at Yale University in human 13C-MRS techniques, which permit direct assessment and metabolic modeling of brain Glu flux in neurons or astrocytes, is proposed for future studies examining specific developmental effects of nicotine. Intensive course work in the fundamentals of MRS, coupled with mentor-guided training in conducting MRS studies of adolescents, drug addiction research methods, professional training in tobacco treatment, and clinical exposure to drug dependent adolescents form the core of this staged career development training plan. Currently, few substance abuse researchers have a background in developmental neuroscience and a practical understanding of MRS, a noninvasive, powerful tool to study neurotransmitter changes induced by stimulant exposure in humans. The application, therefore, provides the candidate with an optimal scientific environment for training, career development and research focused on the persistent problem of adolescent nicotine dependence.