Charles Mactutus
Ph.D.

            NeuroAIDS:

Intravenous drug use among women is often associated with more frequent high-risk sexual behavior, placing them at risk not only for unwanted pregnancy, but also for contracting HIV infection. Given the intractable methodologi­cal and interpretative problems inherent in human developmental research on drug abuse as well as HIV/AIDS, appropriate animal models offer an unique oppor­tunity. The recent establish­ment of a technically simple, economical and practical technique for chronic IV studies in which a vascular port is implanted, prior to mating, offers a model for pregnant rats which rea­sonably mimics the route, pharmacokinetics and expected physiological effects of cocaine abuse in humans via inhalation or IV administration. Our hypothesis is that: Neonatal exposure to the HIV proteins, gp120 and Tat, will produce specific neurodevelopmental disruptions and that these disruptions will be exacerbated by prior in utero cocaine. First, the relative contributions of the interactive effects of IV cocaine and HIV proteins (gp120/Tat) on the developing central nervous system of perinatal animals will be addressed using both well-established in vivo and in vitro procedures. Second, the nature and extent of the structural and functional alterations in the central noradrenergic system will be examined as a potential basis of synergistic effects of IV cocaine and HIV proteins (gp120/Tat). Third, the potential disruption of key developmental processes – neurogenesis and cell death – will be ascertained in a well-characterized model system that undergoes extensive postnatal development - the cerebellum. Thus, this project will 1) contribute to our understanding of the individual and interactive mechanisms of gp120/Tat and cocaine neurotoxicity in a clinically relevant rodent model and 2) further provide a comprehensive examination of potential neuronal/glial targets responsible for early developmental disorders independent of secondary opportunistic infections. These studies will also 3) provide the foundation for an examination of these very same potential mechanisms for cocaine/HIV protein neurotoxicity in humans with the use of fetal autopsy tissue from pregnant chronic IV drug abusers. Our rodent model of IV cocaine, in combination with HIV protein neurotoxicity, is innovative and will be translational to the mechanisms of neuropathology in pediatric AIDS.

122 Tobacco and Health Research Bldg., Lexington, KY 40536-0082 - Phone (859) 257-4788 - Fax (859) 323-1077