MECHANISMS OF COCAINE ACTION ON THE DEVELOPING BRAIN

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Newborn infants exposed to cocaine in utero exhibit behavioral and neurological abnormalities that may hamper their subsequent development. Enabling clinicians to effectively predict and treat these deficits requires knowledge about the mechanisms of cocaine action on the fetal brain, which can be obtained most readily from neurobiological research on animals. Previous studies in our laboratory using the rat as a model animal have shown that cocaine binding sites are present in fetal brain and that cocaine inhibition of synaptic dopamine (DA) uptake occurs prenatally, but that cocaine does not acutely inhibit catecholamine synthesis as it does in adults. The deleterious effects of prenatal cocaine exposure may arise in part from interaction of the drug with these binding sites and subsequent interference with monoaminergic development. Therefore, the overall goals of the proposed studies are to further define the fundamental prenatal mechanisms of cocaine action, to investigate the neurochemical affects of chronic prenatal cocaine treatment, and to relate these effects to possible behavioral alterations in cocaine-exposed animals. Specifically, we will first determine the kinetic characteristics of cocaine receptors pre- and postnatally and localize these receptors autoradiographically using 3H-CFT, a newly available cocaine analog well suited for binding studies. As cocaine receptors in adult organisms have been related to membrane transport systems for DA, norepinephrine (NE), and serotonin (5-HT), we will look for a similar relationship in fetuses by examining the effects of lessening monoaminergic nerve terminals with selective neurotoxins, and by correlating drug inhibition of synaptosomal monoamine uptake with inhibition of CFT binding. Because of the central role of uptake inhibition in mediating the physiological and behavioral effects of cocaine, we will study the prenatal developmental of synaptosomal uptake processes or DA, NE, and 5-HT, and determine the ontogeny of cocaine action on these processes and its potency at various developmental stages. Finally, we will investigate the short- and long- term effects of chronic prenatal cocaine treatment on cocaine receptors, transmitter uptake systems and uptake inhibition by cocaine, D1 and D2 receptors, and selected behaviors that are stimulated by cocaine and mediated by dopaminergic mechanisms. The potency of cocaine in suppressing isolation-induced distress vocalizations will be studied in prenatally cocaine-exposed pups, whereas other animals maintained into adulthood will be tested for place conditioning using i.v. cocaine injection as the reinforcer. By examining a multitude of related neurochemical parameters along with cocaine-stimulated behavioral responses in our prenatally- treated subjects, we expect to find specific neural alterations that have demonstrable functional consequences for the animals.