The overall objective of this proposal is to establish an animal model system which will be useful for investigating the effects of cocaine exposure on the developing brain. Specifically, a technique for artificially rearing neonatal ras will be used to characterize neuromorphological changes resulting from cocaine exposure during the brain growth spurt, the period of most rapid brain growth. That period, which is roughly equivalent to that of the human third trimester, is a time when the developing brain is especially vulnerable to the effects of other insults. The first objective will be to determine basic developmental pharmacokinetic properties of cocaine in the neonatal rats using the artificial-rearing procedure. The first hypothesis to be tested is that cocaine exposure during the brain growth spurt can produce stunted brain growth (microencephaly) either on a temporary or permanent basis. The second hypothesis is that cocaine exposure during the brain growth spurt causes reductions in neuronal populations, and that neurons in various brain regions exhibit differential vulnerability to cocaine. State-of-the-art stereological counting techniques will be used to provide accurate quantitative estimates of entire populations of pyramidal and granule cells in the hippocampal formation, and Purkinje and granule cells in the cerebellum. The third hypothesis to be tested is that cocaine exposure during the third trimester equivalent results in vascular disruption and reactive astrogliosis especially in the neocortex. Glial fibrillary acidic protein (GFAP) immunocytochemistry will be used to identify affected regions throughout the brain. The elucidation of the types and loci of structural brain damage resulting from cocaine exposure during the brain growth spurt will be helpful in identifying stages of development when the brain is especially vulnerable to cocaine and in determining whether the pattern and timing of the cocaine exposure influences the type or extent of damage. These studies will also contribute to establishing a comprehensive picture of the spectrum of structural damage to the mammalian brain that can occur following cocaine exposure during the period of its most rapid development.
