To date thousands of infants and children have been exposed to cocaine prenatally through maternal drug abuse. Since the neurobehavioral consequences of this exposure are difficult to study in clinical populations, appropriate animal models are necessary. The proposed studies will examine the subacute effects of cocaine on developing rat brain following an exposure pattern which we have shown produces long-term alterations in behavior and neurochemistry. In addition, since cocaine has complex pharmacologic actions which may operate individually or collectively to produce these long-term alterations, we will examine three pharmacologic actions of cocaine including: the local anesthetic effects, the inhibition of dopamine (DA) reuptake and inhibition of serotonin (5-HT) uptake. Each agent will be compared using neurochemical and neurobehavioral measures in perinatal and adult animals. By identifying the effects of cocaine and each of its pharmacologic properties in developing brain, the early steps in the cascade of events which ultimately produce cocaine's long-term effects can be identified.
AIM 1) The local anesthetic effects of cocaine will be examined by administering either cocaine or lidocaine, a drug with relatively pure local anesthetic actions, during early PoN life in the rat. The neurobehavioral consequences of these exposures will be measured in periweanling and adult animals by examining startle reflex or administering the DA agonists, quinpirole and SKF 38393, and measuring activity.
AIM 2) The DA effects of cocaine will be measured by treating developing animals with either cocaine or the DA reuptake inhibitor, GBR 12909. Brain functional studies will be conducted 30 minutes after the last of 10 injections and in animals withdrawn from the acute effects of the drugs. Follow-up studies will examine behavioral responses to quinpirole and SKF 38393 as well as startle responsivity.
AIM 3) The effects of cocaine as an inhibitor of 5-HT reuptake will be determined in developing brain by comparing cocaine with fluoxetine, a selective 5-HT uptake inhibitor. Brain functional studies will be conducted as initial studies and follow-up studies will examine behavioral responses to 5-HT-specific agonists, 8-OH-DPAT and DOI, in activity and startle paradigms. By identifying the functional responses to cocaine and each pharmacologic agent, we will enhance our understanding not only about cocaine's effects on developing brain, but also about basic developmental processes.
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