Heavy Metal and Drug Self-Administration: Mechanisms

描述(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，以及有时对可卡因等非法药物产生协同作用和拮抗作用。在现象学水平上已经确定，药物摄取模式和对常见滥用药物的行为反应可能会受到金属暴露的影响。对于发育中的铅暴露来说尤其如此，这种影响是长期存在的，并在暴露方案停止后很长一段时间内持续到成人的生命周期。这一更新应用特别令人感兴趣的是，当铅在怀孕和哺乳期(围产期暴露)期间从母鼠重新分配到幼崽身上时，可卡因的自我给药维持在太低的药物剂量，不能维持非暴露对照组的反应。此外，在围产期暴露于铅的动物中，重新吸毒的可能性更大。目前尚不清楚的是铅暴露动物对可卡因的选择和使用增加的作用机制。在本申请中，建议采用三种方法在雄性和雌性动物中探索铅/可卡因相互作用的问题；1)在药物挑战的框架内，使用微透析技术检测围产期铅暴露对参与可卡因奖赏的关键神经递质[伏隔核(NAC)内的多巴胺(DA)和谷氨酸(Glu)]水平的影响；2)使用标准的放射结合分析方法，将检测发育过程中暴露于铅的动物的NAC和前额叶皮质(RFC)中DA和Glu的结合；3)利用原位杂交技术，将处理动物以寻找类似DA D1、类似DA D2和DA转运体(DAT)的mRNA表达。同样，将评估暴露于铅的动物体内谷氨酸受体的表达。这些终点将在接受应答性或有可卡因、非或有生理盐水或非或有可卡因静脉注射的动物身上进行检查。快递。这项提案与公共卫生的相关性在于，它旨在将构成重大健康风险的两个重大事件联系起来，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会增加吸毒成瘾的脆弱性。

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.