The work outlined in this proposal will examine both the behavioral teratogenic and neuroteratogenic potential of cocaine. The first specific aim of the proposed work is to determine appropriate dose levels in the test population (SpragueDawley rats) that result in cocaine plasma levels of 150300 ng/ml, 400600 ng/ml, and 800-1000 ng/ml, plasma cocaine levels which encompass the range of typical human use patterns. Using these doses, the second specific aim will examine the potential behavioral teratogenic effects of cocaine using not only conventional apical tests of general FUNCTIONAL effects (e.g., physical growth and maturation, reflexes, learning/retention, etc.), but also other BEHAVIORAL measures that appear to be modulated by alterations in activity of specific neurotransmitter systems hypothesized to be influenced by prenatal treatment with cocaine. The third specific aim is to assess more directly neural consequences of prenatal cocaine treatment through both PSYCHOPHARMACOLOGICAL and NEUROCHEMICAL investigations. The specific neurotransmitter systems chosen for investigation are those known to be affected by cocaine exposure in adulthood (i.e., the monoaminergic systems and the cholinergic system to a lesser extent), given that neural systems affected by early drug exposure are often some of the same neural systems affected by exposure to the drug in adulthood (although the nature of the alterations may vary substantially). The emphasis of the work outlined in this proposal is on assessment of the outcome of prenatal cocaine exposure during the early postnatal period, analogous to the age period typically examined in clinical investigations. Thus the strategy underlying this work varies from that used in conventional behavioral teratogical investigations not only in the inclusion of behavioral tests beyond mere apical tests of functional effects, but also by the emphasis on extensive neurobehavioral assessment during the early postnatal period. The multifaceted nature of the work outlined in this proposal, including not only behavioral but also psychopharmacological and neurochemical assessments, will not only address the question of WHETHER cocaine is a neurobehavioral teratogen, but also HOW cocaine influences various target neural systems in relation to the observed behavioral outcome.
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