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自我给药的方式，并对可卡因等非法药物产生协同作用和拮抗作用。从现象学的角度来看，药物摄入模式和对常见滥用药物的行为反应可能受到金属接触的影响。在发育阶段接触铅的情况尤其如此，其影响是持久的，在接触方案停止后很长一段时间内仍会持续到成年人的生命周期。对这一新应用特别感兴趣的是，当铅在妊娠和哺乳期（围产期暴露）从母鼠重新分配给幼崽时，可卡因自我给药维持在药物剂量过低而无法在未暴露的对照组中维持反应。此外，在围产期接触铅的动物中，药物寻求复发的可能性更大。目前尚不清楚的是，在铅暴露的动物中，增加可卡因的选择和使用的作用机制。在本应用中，建议采用三种方法探讨雄性和雌性动物中铅/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水平的影响[伏隔核（NAc）内的多巴胺（DA）和谷氨酸（Glu）], 2)使用标准放射性结合试验，将在发育中暴露于铅的动物中检查NAc和前额皮质（RFC）中DA和Glu的结合，3)以及采用原位杂交技术，将对动物进行DA d1样、DA d2样和DA转运体（DAT） mRNA的表达处理。同样，Glu受体的表达将在铅暴露的动物中进行评估。这些终点将在接受反应偶然的可卡因、非偶然的生理盐水或非偶然的可卡因静脉注射的动物中进行检查。这一建议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，即铅污染和可卡因使用联系起来。根据现有文献，有理由相信环境污染物可能会增加吸毒成瘾的易感性。

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.