The scientific community is increasingly aware that environmental toxicants interact with psychoactive drugs, and affect drug selection and use. Of particular concern are the effects of metals such as lead that shift patterns of drug self-administration, and occasion synergistic as well as antagonistic effects on illicit drugs such as cocaine. It is established at a phenomenological level that patterns of drug intake and behavioral responsiveness to commonly abused drugs may be influenced by metal exposure. And this is especially true for developmental exposure to lead, where the effects are long-lasting and persist into the adult life cycle long after the exposure regimen has been discontinued. Of particular interest to this renewal application is the finding that when lead is redistributed from the dams to the pups during gestation and lactation (perinatal exposure), cocaine self-administration is maintained at drug doses too low to sustain responding among nonexposed controls. Moreover, relapse to drug seeking is more likely in animals perinatally exposed to lead. What is not understood is the mechanism of action for increased selection and use of cocaine in lead-exposed animals. In this application it is proposed that the issue of lead/cocaine interactions be explored in male and female animals employing three approaches; 1) examine the effects of perinatal lead exposure on the levels of key neurotranmitters involved in cocaine reward [dopamine (DA) and glutamate (Glu) within the nucleus accumben (NAc)] using microdialysis techniques within a framework of drug challenges, 2) using standard radiobinding assays, binding of DA and Glu in the NAc and prefrontal cortex (RFC) will be examined for animals developmentally exposed to lead, 3) and, employing in situ hybridization techniques, animals will be processed for DA D1-like, DA D2-like, and DA transporter (DAT) mRNA espression. Similarly, Glu receptor expression will be assessed in lead-exposed animals. These endpoints will be examined in animals that have received response contingent cocaine, noncontingent saline, or , noncontingent cocaine i.v. deliveries. The relevance of this proposal to public health is that it aims to link two major events that pose significant health risks, i.e., lead contamination and cocaine use. Based on the available literature, there is reason to believe that environmental pollutants may increase vulnerability to drug addiction. ? ? ?
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