PSYCHOMOTOR STIMULANTS AND DOPAMINE RECEPTOR DEVELOPMENT

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The incidence of infants born with illicit substances in their urine has increased greatly over the past 10 years, primarily due to an increase in the use of psychomotor stimulants (PMS) such as cocaine (COC) and methamphetamine (MAP). As more of these children are born, animal studies to determine the consequences of perinatal exposure to these drugs become more important. The long term goal of the research program is to examine the neurochemical and behavioral consequences of PMS exposure at various times during rat development to model the stages of human pregnancy. For this proposal, drug exposure will be limited to the early postnatal period of the rat to model third trimester human exposure. Third trimester administration of drugs acting at the synapse is particularly damaging because this period is characterized by synaptogenesis and dendritic arborization. Perinatal PMS exposure is known to have adverse effects on neurobehavioral development. These drugs alter dopamine (DA) and serotonin (5-HT) levels in the brain by causing release from and/or blocking uptake into the presynaptic neuron. Because DA and 5-HT act as growth regulators, altered levels during development may alter normal synaptogenesis. MAP treatment is also reported to destroy DA neurons with chronic treatment. DA depletion during development produces behavioral disorders in animals, with the type and range of disorders depending upon timing of the lesion. The aims of this proposal are to determine if: (1) PMS treatment during critical periods of development has permanent effects on DA system; (2) If so, are the effects dependent upon the timing of the drug treatment; and (3) Do they involve alterations in the intrinsic organization f he striatum, known as the patch/matrix organization. Rat pups will be treated wit COC or MPA at different time periods during the first week of life. The behavioral and neurochemical consequences of PMS treatment will be examined. Quantitative receptor autoradiography will be used to quantify and localize DA receptors in the adult brain. Markers of the presynaptic terminal will be used to determine if drug treatment has permanent effects on DA neurons. In situ hybridization histochemistry will be used to measure mRNA levels coding for tyrosine hydroxylase (the synthetic enzyme for DA), as a sensitive indicator of neuronal damage. Immunocytochemical and histochemical marker of the patch and matrix compartments will be used to determine if early PMS treatment disrupts the development of the intrinsic organization of the striatum. Behavioral function will be examined by looking at responses to selective DA receptor agonist and antagonist, as well as cognitive tests and tests for the presence of sensitization. A preliminary examination of serotonergic function will be carried out because PMS are known to affect 5-HT levels. The results of this study will provide the starting point for a long-term research program interested in examining the neurochemical and behavioral effects of PMS exposure during the various stages of development. This work should aid in our understanding of the consequences of perinatal drug exposure, and give us insights into the development of intervention strategies for infants exposed to PMS.