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

描述（由申请人提供）：项目摘要/摘要：这是一个GO申请，旨在将“酒精和尼古丁共同依赖的机制”作为科学优先领域。使用GO机制是因为该应用需要多实验室方法来加速当前和未来的研究。本提案的目的是更好地了解乙醇（EtOH）和尼古丁（NIC）在促进共同滥用方面的增强作用相互作用的机制。待检验的总体假设是，EtOH或NIC给药将对另一种药物的强化作用产生交叉致敏作用，从而促进其共同滥用的可能性。腹侧被盖区（VTA）是支持EtOH和NIC的强化作用的部位，并且是研究EtOH和NIC相互作用的极好起点。由于遗传因素导致饮酒和吸烟的滥用可能性，因此将使用已证明EtOH和NIC滥用均独立的动物模型，即，选择性繁殖的酒精偏好（P）大鼠。操作技术将用于颅内自我给药和NIC静脉自我给药实验。微透析-HPLC程序将用于测量多巴胺（DA）和谷氨酸的细胞外水平。将使用定量RT-PCR测量靶基因表达变化。目的是确定EtOH和NIC给药对中脑边缘系统对其他药物增强作用的敏感性的影响，如果这些增强作用与DA神经元对药物的反应增加有关，以及EtOH和NIC是否协同相互作用。另一个目的是建立EtOH和NIC共同滥用的动物模型，并确定EtOH和NIC共同滥用对DA，GABA，谷氨酸，5-HT和烟碱系统的成瘾相关受体或受体亚基基因表达的影响。另一个目的是确定与EtOH和NIC共同滥用相关的中脑边缘系统内DA和多巴胺能神经元通路的活性变化。总的来说，该项目的结果将提供更好的理解的神经生物学基础的相互作用的EtOH和NIC，有助于他们的共同滥用。这是制定治疗策略以减少其使用和共同滥用的重要第一步。由于饮酒和吸烟影响数百万人，该项目对改善许多人的健康和生活具有潜在的深远影响。 公共卫生相关性：同时使用酒精和烟草是常见的，影响数百万人。当一起使用时，酒精和烟草会加剧单独使用时发现的健康风险。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，以便制定治疗策略以减少或预防其使用。

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.