Altering Neuroplasticity During Development: Impact on Substance Abuse in the Adult. This project tests the hypothesis that mechanisms of neural plasticity are key determinants of allphases of addiction, including the initial susceptibility to drug-taking behavior. Therefore, it asks whetheraltering neural plasticity during development will in turn alter the behavioral response to cocaine and/or itsneural consequences at various stages of drug exposure. It further asks whether the impact of thisdevelopmental manipulation will be different in animals selectively bred based on the novelty-seeking trait tobe either high responders (HR) or low responders (LR). This trait has been linked to differences in both initialsusceptibility to self-administer drugs and differences in hippocampal neurogenesis, with the HR animalsbeing more prone to drug-taking and showing lower rates of neurogenesis. We propose to use a developmental manipulation that enhances hippocampal neurogenesis - i.e.theneonatal administration of the Fibroblast Growth Factor 2 (FGF2). Thus, HR-bred and LR-bred animals willeither receive vehicle or a small dose of FGF2 on the first day of life. They will be raised to adulthood andthen exposed to cocaine either through experimenter administration or self-administration, followed byvarious periods of abstinence. The impact of a social stressor on their behavior and neural responses willalso be tested. We hypothesize that neonatal FGF2 treatment will lead to 'protection' against drug abuse both underbasal and under stress conditions. We further hypothesize that the protective effect will be more marked inthe novelty-seeking HR-bred animals under basal conditions, and in the LR-bred animals under stressconditions. The neural dependent variables to be tested included hippocampal morphology and rates ofneurogenesis. They also include assessment of gene expression in the hippocampus and nucleusaccumbens (core and shell) using a panel of genes relating to neural plasticity, including the stress, growthfactor and synaptic remodeling genes studied in the other three projects. The results of this project will yieldinformation on antecedents of drug abuse vulnerability during early development in animals with differinggenetic susceptibilities to drug seeking.
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