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

项目概述/摘要：这是一项GO应用程序，旨在解决“酒精和尼古丁共同依赖机制”作为科学优先领域。使用GO机制是因为该应用程序需要多实验室方法来加速当前和未来的研究。本研究的目的是为了更好地了解乙醇（EtOH）和尼古丁（NIC）在促进共同滥用中的强化作用的相互作用机制。要测试的总体假设是，施用EtOH或NIC会对另一方的强化效应产生交叉敏化，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。由于遗传因素有助于酗酒和吸烟的滥用潜力，因此将使用一种已经独立证明EtOH和NIC滥用的动物模型，即选择性繁殖的酒精偏好(P)大鼠。采用操作技术进行脑内给药和静脉给药实验。微透析-高效液相色谱程序将用于测量细胞外多巴胺（DA）和谷氨酸的水平。定量RT-PCR检测目标基因表达变化。目的是确定EtOH和NIC给药对中边缘系统对其他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EtOH和NIC共同滥用的动物模型，确定EtOH和NIC共同滥用对DA、GABA、谷氨酸、5-HT和尼古丁系统成瘾相关受体或受体亚基基因表达的影响。另一个目的是确定中边缘系统中与EtOH和NIC共同滥用相关的DA和谷氨酸能神经元通路活性的变化。总的来说，本项目的结果将更好地了解EtOH和NIC相互作用导致其共同滥用的神经生物学基础。这是朝着制定减少它们的使用和共同滥用的治疗策略迈出的重要的第一步。由于酗酒和吸烟影响到数百万人，因此该项目对改善许多人的健康和生活具有潜在的深远影响。

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.