The work outlined in this proposal will examine further the neurobehavioral consequences of early cocaine exposure. Two of the most robust behavioral alterations observed during the previous project period in offspring of sprague-Dawley dams exposed subcutaneously to cocaine from gestational days 8-20, relative to offspring of pair-fed and untreated control dams, were; (a) their unusual behavioral response to stressors and (b) the cognitive deficits they exhibit in complex or presumably stressful testing situations. Apparent attenuations in dopamine (DA) activity were observed on some response measures, but not others, leading to the hypothesis that the underlying DA deficiency may be functionally countered by neural compensatory processes under basal conditions, but may be """"""""unmasked"""""""" under challenging or stressful test circumstances. The work outlined in this proposal will examine the alterations in cocaine-exposed offspring under these two types of """"""""challenges,"""""""" with an emphasis on possible alterations in DA function as contributing factors to these long-term behavioral consequences of gestational cocaine exposure. Experimental Series 1 will examine the behavioral responses to acute stressors in adult offspring prenatally exposed to cocaine as well as their behavioral, neurochemical and hormonal response to acute and repeated stressors. The intent of these studies is to evaluate in what ways the behavioral responsivity to stressors has been altered by prenatal cocaine exposure, and to determine whether similar alterations in stress responsivity are seen using hormonal and neurochemical response measures, with a particular emphasis in the latter on assessment of alterations in responsiveness of the DA systems to stressors. Experimental Series 2 will focus further on behavioral assessments in these offspring. The first studies in this series will examine whether adult cocaine-exposed offspring exhibit not only deficits in reversal performance, but alterations in other behaviors that have been associated with disruption of DA terminal regions. The second part of this series will examine in more detail the cognitive alterations in these offspring by assessing what behavioral features and processes lead to their alterations in cognitive performance. At this early stage in the investigation of the developmental toxicology of cocaine, such animal research is critical to confirm and extend potentially confounded clinical findings, to anticipate other potential consequences of early cocaine exposure, as well as to offer insights into the mechanisms influencing the developmental outcome of the large number of children that have been exposed prenatally to this drug of abuse.
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