Functional magnetic resonance imaging (fMRI) of the brain has improved our understanding of drugs of abuse. Progress in applying this approach to conscious animals has been slow because subjects must be immobile during imaging. We have invented a device that allows us to image rodents while awake, opening new opportunities to study brain function non-invasively over time. Repeated exposure to drugs of abuse evokes a progressive increase in locomotor stimulation, termed behavioral sensitization. It is thought that sensitization is central to addiction to drugs, including nicotine. This resubmission addresses two potentially important observations about nicotine sensitization. First, it can be imaged with fMRI, allowing identification of the brain structures involved. The role of individual neurotransmitters in sensitization can be evaluated through the administration of selected receptor agonists to sensitized animals during imaging. Our preliminary data indicate that fMRI can be used to determine the role in sensitization to glutamate receptors in various brain regions.
The aims of this proposal are 1) to determine if the administration of nicotine to sensitized animals produces alterations in neuronal activity in the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, ventral pallidum, anterior cingulate gyrus, septum and visual cortex as measured by blood oxygen level-dependent contrast (BOLD);2) to determine how long nicotine sensitization persists;3) to determine how the administration of monoamine oxidase inhibitors in conjunction with nicotine alters the persistence of sensitization;and 4) to investigate the role of glutamate in the expression of sensitization. This proposal is highly innovative in the use of fMRI to study sensitization. Once developed, this technique could be used to translate our knowledge of sensitization in animals to the study of sensitization in humans and its relation to addiction. The imaging of sensitization may provide a powerful new tool for the exploration of novel pharmacologic approaches to treating nicotine addiction, which is the largest contributor to preventable mortality in the developed world.
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