This is a revision of the renewal application to further investigate neurobehavioral effects of developmental AZT (zidovudine) exposure in a rat model. Although AZT was not structurally teratogenic following perinatal exposure, this group found that specific neurobehavioral alterations were produced. In particular, the acoustic startle response was increased in 75 day old adults challenged with amphetamine following perinatal AZT exposure. On the other hand, open field behavioral responses to amphetamine challenge in these same perinatally exposed rats were transiently altered but were within normal range by 60 days of age. Therefore, the proposed experiments will further probe the altered acoustic startle response using both pharmacologic and psychophysical approaches. In addition, the neuroanatomic basis for the altered startle response will be determined by conducting functional imaging experiments in the animals responding to the startle stimuli. Functional changes in brain and spinal cord will be correlated with the distribution and density of major neurotransmitter receptors known to be involved in the startle response. Since several new therapies are now currently used alone or in combination with AZT and little is known about their developmental toxicity, these new therapies 3TC (lamivudine) and nelfinavir will also be studied for developmental toxicity with a focus on neurobehavioral effects. 3TC (a nucleoside analogue) and nelfinavir(a protease inhibitor) will be administered throughout pregnancy and during the postnatal period of brain development. The structural and neurobehavioral teratogenesis will be assessed. In addition, the 3TC and nelfinavir exposed cohorts will be held to monitor general health and incidence of pathological alterations up to one year of age. In this way, the possible adverse effects on growth and development, including neurobehavioral, teratogenic and tumorigenic effects, of these commonly used drugs can be determined in an animal model and potentially damaging effects in children at risk for HIV exposure can be avoided.
