Cocaine Impact on Neural Plasticity: Modulation by Genetic Vulnerability & Social Stress. This project tests the hypothesis that a major impact of cocaine on the brain is to alter the expressionof genes relating to neural plasticity in reward and stress-related circuits, and to affect hippocampalmorphology and neurogenesis. The proposed studies will use two lines of animals selectively bred for twelvegenerations for the novelty-seeking trait (high responders-HR versus low responders-LR). This trait relates togeneral reactivity to the environment including 'novelty-seeking' behavior, and predicts initial likelihood toself-administer drugs. The selectively bred animals will be exposed to cocaine, followed by various periods of abstinenceusing two methods of cocaine delivery: Self-Administration and Experimenter Administration. They will betested either under control conditions or following a social stressor. The differential impact of these manipulations will be assessed by measuring altered expression of apanel of growth factor genes, stress genes and synaptic plasticity genes in two regions of the hippocampus(HC) and in the core and shell of the nucleus accumbens (NAcc). The choice of the target genes was basedon a combination of existing literature findings and our own data based on microarray profiling after socialstress and drug self-administration. Associated changes in hippocampal morphology and neurogenesis willbe studied at each of'these phases. Of particular interest will be those drug-related genes whose alterationsare sustained long after drug administration has ceased, as they may point to mechanisms of enduringeffects of substance abuse that would lead to relapse. Promising genes will be functionally characterized by protein analysis and pharmacologicaladministration of agonists, antagonists or analogues to assess their potential role in modulating the sequelaeof exposure to cocaine in animals with differing susceptibility to the drug. This work should lead to new discoveries regarding the molecular mechanisms of addiction andprovide novel targets for its treatment.
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