The recent establishment of a technically simple, economical, and practical techniques for chronic IV studies in which a vascular port is implanted prior to mating, offers a model for pregnant rats which reasonably mimics the rapidly peaking pharmacokinetics profile of cocaine abused via inhalation or IV administration. The proposed program specifically addresses the major question: Is maternal cocaine abuse during pregnancy a neurobehavioral teratogen when administered via a clinically-relevant route? The specific aims of the program are: 1) To determine the biodistribution of cocaine in the pregnant dam/fetus following intravenous administration. Using an IV vascular access port in unanesthetized pregnant rats we will determine both plasma and brain levels in dam and fetus of cocaine and its major metabolite, benzoylecgonine. Both time-response and dose-response functions will be determined. These studies are of fundamental importance in establishing the magnitude and duration of fetal cocaine exposure following maternal IV administration. 2) To establish the nature and extent of neurobehavioral alterations which occur in the offspring consequent to intravenous maternal cocaine exposure during pregnancy. Using unanesthetized IV-catheterized pregnant rats we will conduct ontogenetic and longitudinal analyses of the neurobehavioral effects of maternal cocaine exposure on the offspring with the inclusion of nutritional controls and surrogate fostering. These studies will identify dose-response functions and critical exposure periods. The dissociation of specific cognitive deficits from sensory or motor impairments will also be provided by the use of both multiple tasks and multiple dependent measures within each task. 3) To establish the nature and extent of the structural and functional alterations in the central noradrenergic system which occur following intravenous maternal cocaine exposure during pregnancy. Quantitative neuroanatomical measurements, quantitative protein analysis (Western blotting), synthetic enzyme activity, and in situ hybridization will be utilized to assess the structural and functional integrity of the central noradrenergic system. As a putative target of maternally administered cocaine, we hypothesize that alterations in the central noradrenergic system may be the neurobiological mechanism underlying the persistent and selective alterations observed in behavior, as particularly evident in """"""""attentionally sensitive"""""""" neurobehavioral paradigms. The goals of the proposed program are to program are to provide a characterization of the neurobehavioral effects of maternal cocaine abuse during pregnancy, in an animal model based upon the clinically-relevant IV route of administration, and to characterize a neurobiological mechanism potentially underlying the persistent and selective neurobehavioral alterations.
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