Heavy Metal and Drug Self-Administration: Mechanisms

描述（由申请人提供）：科学界越来越意识到环境毒物与精神活性药物相互作用，并影响药物的选择和使用。特别令人关切的是，铅等金属的影响改变了药物自我给药的模式，有时对可卡因等非法药物产生协同作用和拮抗作用。它是建立在现象学水平上的药物摄入和行为反应的模式，通常滥用药物可能会受到金属暴露。对于发育期接触铅尤其如此，其影响是持久的，在接触方案停止后很长时间内都会持续到成年人的生命周期。特别感兴趣的是，这一更新申请的发现，当铅从母鼠重新分配到幼鼠在妊娠期和哺乳期（围产期暴露），可卡因自我管理维持在药物剂量太低，以维持响应之间的非暴露的控制。此外，在围产期暴露于铅的动物中，更有可能复发寻求药物。目前尚不清楚的是，在接触铅的动物中增加可卡因的选择和使用的作用机制。在这项申请中，建议采用三种方法在雄性和雌性动物中探讨铅/可卡因相互作用的问题; 1）在药物挑战的框架内，使用微透析技术检查围产期铅暴露对可卡因奖励中涉及的关键神经递质[多巴胺（DA）和谷氨酸（Glu）]水平的影响，2）使用标准放射结合测定，将检测发育中暴露于铅的动物的NAc和前额叶皮层（RFC）中DA和Glu的结合，3）并且采用原位杂交技术，将处理动物以进行DA D1样、DA D2样和DA转运蛋白（DAT）mRNA表达。同样，将在铅暴露动物中评估Glu受体表达。将在接受反应相关可卡因、非相关生理盐水或非相关可卡因静脉输注的动物中检查这些终点。这项建议与公共卫生的相关性在于，它旨在将两个构成重大健康风险的重大事件联系起来，即，铅污染和可卡因使用。根据现有的文献，有理由相信环境污染物可能增加吸毒成瘾的可能性。

DESCRIPTION (provided by applicant): 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.