Ethanol and nicotine co-abuse: cross sensitization of their reinforcing actions

描述(由申请者提供)：项目摘要/摘要：这是一个将“酒精和尼古丁相互依赖的机制”作为科学优先领域的GO申请。使用GO机制是因为这项应用需要多实验室方法来加速当前和未来的研究。这项提议的目的是为了更好地了解乙醇(EtoH)和尼古丁(NIC)在促进共同滥用方面的增强效应相互作用的机制。需要检验的总体假设是，给予乙醇或NIC会对另一种药物的强化作用产生交叉敏感化，从而促进它们共同滥用的可能性。腹侧被盖区(VTA)是支持EtoH和NIC增强作用的部位，是研究EtoH和NIC相互作用的良好起点。由于遗传因素导致饮酒和吸烟的滥用可能性，将使用一种独立证明乙醇和NIC滥用的动物模型，即选择性繁殖的偏爱酒精(P)大鼠。手术技术将用于颅内自我给药和静脉注射。网卡自主管理实验。微透析-高效液相程序将被用来测量细胞外多巴胺(DA)和谷氨酸的水平。靶向基因表达的变化将通过定量RT-PCR进行测量。目的是确定乙醇和NIC给药对中脑边缘系统对另一种药物增强效应的敏感性的影响，这些增强效应是否与DA神经元对药物的反应增加有关，以及EtoH和NIC是否协同作用。另一个目的是建立乙醇和NIC共同滥用的动物模型，并确定EtoH和NIC联合滥用对DA、GABA、谷氨酸、5-羟色胺和烟碱系统成瘾相关受体或受体亚单位基因表达的影响。另一个目的是确定中脑边缘系统中DA和谷氨酸能神经元通路的活性变化，这些变化与乙醇和NIC共同滥用有关。总体而言，该项目的结果将为乙醇和NIC的相互作用提供更好的神经生物学基础，这些相互作用有助于它们共同滥用。这是朝着制定治疗策略迈出的重要的第一步，以减少它们的使用和共同滥用。由于饮酒和吸烟影响着数以百万计的人，该项目对改善许多人的健康和生活具有潜在的深远影响。 与公共健康相关：同时饮酒和吸烟很常见，影响了数百万人。当酒精和烟草一起使用时，它们单独使用会增加健康风险。该项目的长期目标是更好地了解酒精和尼古丁共同滥用的大脑机制，以便制定治疗策略来减少或防止它们的使用。

DESCRIPTION (provided by applicant): Project Summary/Abstract: This is a GO application to ddress "Mechanisms of Alcohol and Nicotine Co-Dependence" as the area of scientific priority. The GO mechanism is used because this application requires a multi-lab approach to accelerate current and future research. The objective of this proposal is to provide a better understanding of the mechanisms underlying the interactions of the reinforcing effects of ethanol (EtOH) and nicotine (NIC) in promoting co-abuse. The overall hypothesis to be tested is that administration of EtOH or NIC will produce cross-sensitization to the reinforcing effects of the other, which promotes the potential for their co-abuse. The ventral tegmental area (VTA) is a site supporting the reinforcing actions of EtOH and NIC, and is an excellent starting point for studying the interactions of EtOH and NIC. Since genetic factors contribute to the abuse potential of drinking and smoking, an animal model that has demonstrated both EtOH and NIC abuse independently will be used, i.e., the selectively bred alcohol-preferring (P) rat. Operant techniques will be used for the intra-cranial self-administration and i.v. NIC self-administration experiments. Microdialysis-HPLC procedures will be used to measure extracellular levels of dopamine (DA) and glutamate. Targeted gene expression changes will be measured with quantitative RT-PCR. The aims are designed to determine the effects of EtOH and NIC administration on the sensitivity of the mesolimbic system to the reinforcing effects of the other drug, if these reinforcing effects are associated with increased response of DA neurons to the drug, and whether EtOH and NIC interact synergistically. Another aim is designed to establish an animal model of co-abuse of EtOH and NIC, and to determine the effects of co-abuse of EtOH and NIC on the expression of genes for addiction-associated receptors or receptor subunits for DA, GABA, glutamate, 5-HT and nicotinic systems. Another aim is designed to identify changes in the activity of DA and glutamatergic neuronal pathways within the mesolimbic system that are associated with EtOH and NIC co-abuse. Overall, the results of this project will provide a better understanding of the neurobiological basis for the interactions of EtOH and NIC that contribute to their co-abuse. This is an important initial step toward developing treatment strategies to reduce their use and co-abuse. Since alcohol drinking and smoking affect millions of people, this project has potential far reaching impact on improving the health and lives of many individuals. PUBLIC HEALTH RELEVANCE: The co-use of alcohol and tobacco is common and affects millions of people. When used together, alcohol and tobacco compound the health risks found with their individual use. The long-range goals of this project are to better understand the brain mechanisms underlying the co-abuse of alcohol and nicotine, so that treatment strategies can be developed to reduce or prevent their use.