THE DEVELOPMENT NEUROCHEMISTRY OF COCAINE

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The long-term goals of this work are to develop treatments for cocaine abuse, as well as for children with neurobehavioral abnormalities resulting from prenatal exposure to cocaine. Specifically, this project will (1) investigate the neurochemical and behavioral effects in rats of exposure to various doses of cocaine prenatally and (2) investigate the neurochemical and behavioral responses to intravenous cocaine in rats of varying ages and compare these responses to those of animals which have been exposed to cocaine in utero. It is postulated that prenatal exposure to cocaine can affect development of specific neurotransmitter pathways in the central nervous system. It is also postulated that animals of different ages may respond to cocaine in a different manner. Pregnant females will receive either intravenous injections of various doses of cocaine or saline or no treatment in pregnancy during prenatal development of dopaminergic, noradrenergic, and serotonergic neurons. The neurochemical effects of the above treatments will be studied in the neonate. Additional pups from these treatment groups will be fostered to surrogate dams. The neurochemistry and behavior of these pups will be studied both under control conditions and in response to cocaine in weanling (21 day) and sexually mature (60 day) rats. Male and female pups will be studied to determine if there are sex-related effects of prenatal cocaine exposure. Neurotransmitter content and neuronal activity will be estimated in specific brain regions for the following transmitters: acetylcholine (ACh), dopamine (DA), norepinephrine (NE) and serotonin (5-HT). Cholinergic neuronal activity will be assessed by quantitating ACh turnover by a mass fragmentographic technique that measures the relative incorporation of deuterium label from infused phosphorylcholine precursor into choline and ACh. The activity of DA, NE, and 5-HT neurons will be estimated by quantitating neurotransmitters and their metabolites using HPLC with electrochemical detection. Brain areas to be analyzed are frontal cortex, parietal cortex, hippocampus, striatum, hypothalamus, and medulla-pons. Behavioral testing will consist of measuring weight gain, simple reflexes, locomotor activity and habituation. Once the effect of exposure to cocaine either prenatally or postnatally on neurochemistry is more completely understood, then better treatment can be developed for cocaine abuse and for the neurobehavioral deficits exhibited by those exposed to cocaine prenatally.