Studies estimate that millions of Americans use cocaine regularly, and increasing numbers of cocaine abusing mothers are delivering infants repeatedly exposed to cocaine throughout their development. While gross malformations are not observed in these infants and the initial irritability often observed disappears, there may be important underlying neurochemical abnormalities that will lead to later psychiatric and/or neurological disorders. In animals, cocaine and amphetamine are both known to have """"""""sensitizing"""""""" effects on the brain's dopamine pathways that produce increased behavioral and biochemical responses to a given dose of the drug and persist for weeks to several months. This phenomena has a parallel in human amphetamine use where reexposure to a low dose of amphetamine can precipitate a psychotic episode in former amphetamine addicts who have been abstinent for months to years. Such long-lasting hypersensitivity suggests that chronic exposure to cocaine or amphetamine has long-term effects on brain neurochemistry. Furthermore, chronic exposure to amphetamine in rats has been shown to produce toxic degeneration of the dopamine neurons. The possibility of such a toxic effect has not been systematically examined in infants exposed prenatally to chronic cocaine or amphetamine. Both drugs are likely to have much more deleterious effects on the dopamine pathways during development. The goal of the proposed experiments is to evaluate the impact of chronic prenatal exposure to cocaine or amphetamine on the two major dopamine pathways in the brain, the mesolimbic and nigrostriatal systems. In each dopaminergic pathway the long-term effects of these drugs on transmitter release and reuptake will be evaluated under basal and activating conditions using in vivo measurement techniques. Microdialysis will be used to measure basal levels of dopamine and its metabolites, and changes in these parameters in response to tail pinch and amphetamine. Fast-scan, carbon-fiber voltammetry will be used to examine the kinetic parameters of the dopamine release-reuptake process. The neurotoxic actions of the drugs will be examined by postmortem analysis of the catecholamines and their metabolites in the major dopaminergic projection areas of the brain. These studies should provide critical information concerning the effects of prenatal stimulant exposure on the functioning of dopaminergic neurons.
