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

乙醇和尼古丁共同滥用：其强化作用的交叉敏感性

• 批准号: 7852416
• 负责人: WILLIAM J MCBRIDE
• 金额: $ 134.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7852416
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcohols; Amino Acid Neurotransmitters; Amino Acids; Animal Model; Area; Brain; Breeding; Cephalic; Dependence; Development; Dopamine; Ethanol; Future; Gene Expression; Genetic; Glutamates; Goals; Health; Individual; Intake; Life; Limbic System; Measures; Mediating; Microdialysis; Modeling; Neurobiology; Neurons; Neurotransmitters; Nicotine; Nicotinic Receptors; Pathway interactions; Pharmaceutical Preparations; Procedures; Rattus; Recording of previous events; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Self Administration; Self-Administered; Serotonin; Site; Smoking; System; Techniques; Testing; Tobacco; Ventral Tegmental Area; abstracting; addiction; alcohol effect; base; binge drinking; cholinergic; design; dopamine system; dopaminergic neuron; drinking; extracellular; gamma-Aminobutyric Acid; improved; mesolimbic system; monoamine; neurotransmission; nicotine abuse; prevent; public health relevance; receptor; research study; response; treatment strategy

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.

描述（由申请人提供）： 项目摘要/摘要：这是一项 GO 申请，旨在将“酒精和尼古丁相互依赖的机制”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。该提案的目的是更好地理解乙醇（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。要测试的总体假设是，EtOH 或 NIC 的给药会对另一种的增强作用产生交叉敏感性，从而增加了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，因此将使用已独立证明 EtOH 和 NIC 滥用的动物模型，即选择性繁殖的嗜酒 (P) 大鼠。操作技术将用于颅内自我给药和静脉注射。 NIC自我管理实验。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。将通过定量 RT-PCR 测量目标基因表达变化。目的旨在确定 EtOH 和 NIC 给药对中脑边缘系统对另一种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 是否相互作用协同。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共同滥用对成瘾相关受体或DA、GABA、谷氨酸受体亚基基因表达的影响、5-HT 和烟碱系统。另一个目的是确定中脑边缘系统内 DA 和谷氨酸神经元通路活性的变化，这些变化与 EtOH 和 NIC 共同滥用相关。总体而言，该项目的结果将有助于更好地理解 EtOH 和 NIC 相互作用的神经生物学基础，从而导致二者共同滥用。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：同时饮酒和吸烟很常见，影响着数百万人。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，以便制定治疗策略来减少或防止其使用。