Neurochemistry; Neuropharmacology; Neurobehavioral Effects of Abused Drugs During Development

Cocaine abuse by pregnant women represents a significant health problem in this country, as infants exposed to cocaine in utero may exhibit various behavioral and neurological abnormalities. In my laboratory, we are using the rat as a model animal to determine the mechanisms of cocaine action on the developing brain and the neurochemical and behavioral consequences of chronic prenatal cocaine exposure.

Cocaine action on the adult brain is well established. The compound binds to membrane transporters for dopamine (DA), norepinephrine (NE), and serotonin (5-HT), thereby blocking the synaptic reuptake of these transmitters and potentiating their activity. One of the aims of our research has been to determine whether similar processes occur during prenatal development.

Our studies have demonstrated binding of [3H]cocaine and the cocaine analog [125I]RTI-55 to DA and 5-HT transporters in fetal rat brain. Such binding is functional in that cocaine inhibits DA uptake into nerve terminals during late fetal development with the same potency it exhibits in adulthood.

In vitro autoradiography has also been used to investigate the anatomical localization of [125I]RTI-55 binding sites in fetal and adult brains. Other experiments have shown that the offspring of cocaine-treated mothers exhibit a transient stimulation of tyrosine hydroxylase activity (the rate-limiting enzyme in catecholamine biosynthesis) and a reduction in DA transporter binding in the corpus striatum.

A new direction of our research program is to begin investigating the influence of prenatal cocaine on signal transduction mechanisms in the developing brain.

To this end, we are planning studies of second messenger systems (e.g., DA-sensitive adenylyl cyclase), induction of immediate-early genes such as c-fos, and the trans-synaptic regulation of neuropeptide gene expression in the striatum.

Finally, we have also used behavioral approaches to determine some of the functional effects of prenatal cocaine treatment. Thus far, we have found that rat pups exposed to cocaine in utero show an increased sensitivity to behavioral activation produced by a cocaine challenge given postnatally but are less sensitive to the cataleptic effects of the DA D2 receptor antagonist haloperidol. In future studies, we plan to characterize more fully the responses of such animals to both DA agonists and antagonists.

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