This proposal is a request for a NIDA K02 Independent Scientist Award to allow Dr. Kosofsky to further develop his research program in the field of drug abuse research. Dr. Kosofsky is a K20 award recipient, who has created an animal model (in mice) of the effects of gestational cocaine exposure on brain development. Infants born to mothers who abuse cocaine during gestation demonstrate a significant decrease in head circumference indicative of in utero compromise of brain growth and development. The animal model Dr. Kosofsky developed while being supported by the K20 has identified brain growth, neuroanatomic, behavioral, and neurochemical consequences of transplacental cocaine exposure, and has characterized some of the molecular mechanisms whereby brain is modified. This K02 research proposal outlines a strategy to further our understanding regarding the determinants, correlates and mechanisms underlying the cocaine-induced disruption of brain development. The research program outlines a strategy to utilize knockout mice that have specific deficits in dopaminergic signal transduction to characterize molecular mechanisms which may underlie some of the effects of gestational cocaine exposure in altering brain development. By utilizing knockout mice which have specific elements within the dopaminergic signal transduction pathway rendered inoperative (i.e., dopamine transporter knockouts and D1a receptor knockouts), identification of mechanisms by which dopaminergic-mediated signals are responsible for cocaine-induced alterations in brain structure will be elucidated. Neuroanatomic methods proposed include MRI microscopy, a newly developed technology capable of generating volumetric data sets that can be segmented for morphometric analysis, providing an unprecedented ability to visualize and quantitate 3-dimensional brain structure, and alterations thereof resulting from gestational cocaine exposure. One power of this approach is the combination of a unique biologic preparation (i.e., knockout mice) with an innovative technology (e.g., MRI microscopy), utilized in the service of a clinical problem of fundamental importance. In addition, this grant will contribute significantly to Dr. Kosofsky's career development by offering him the opportunity to further develop his research program on the transplacental effects of cocaine, by innovating and applying these approaches and methods.
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