INTERACTIONS BETWEEN NICOTINE & OTHER CIGARETTE SMOKE COMPONENTS IN SUPPORTING

多年来，关于香烟成瘾特性的研究一直集中在尼古丁（NIC）上;对人类受试者和实验动物的研究提供了令人信服的证据，表明NIC有助于吸烟。然而，现在很清楚，香烟烟雾中4000多种化合物中的其他化学物质也有助于香烟的成瘾性，至少部分是通过与NIC对大脑的影响相互作用。在香烟烟雾中存在的许多化合物中，已经确定的与NIC以重要方式相互作用的化合物不到12种。这些化合物可以被视为适合四个主要类别：一组所谓的次要生物碱（例如，假木贼碱、去甲烟碱）、对咔啉Harman和norharman、乙醛和抑制单胺氧化酶（MAO）的其它化合物。本项目的目标是探索，在一个良好的表征大鼠模型的NIC自我管理，加强作用的NIC的背景下，其他成分的香烟烟雾，可能有助于其滥用的责任。 有四个具体目标：[1]确定烟草成分混合物对NIC自我给药的剂量反应关系的影响。假设：包括次要生物碱、β-咔啉、乙醛和MAO抑制剂的烟草成分的混合物将改变NIC自我给药的剂量-反应曲线，使得NIC在支持自我给药方面更有力和有效。[2]确定改变烟草成分混合物的成分浓度是否会改变NIC自我给药的获得和维持。假设：增加烟草成分混合物中化合物的浓度将增加特定剂量IC的自我给药，而降低浓度将减少自我给药。[3]确定改变烟草成分混合物中化合物的浓度是否可以抵消或促进随时间减少NIC剂量引起的NIC自我给药减少。假设：通过降低混合物成分的浓度，可以增强由降低NIC剂量引起的NIC自身给药的减少，而通过增加这些化合物的浓度，可以减轻（或甚至防止）降低NIC剂量的效果。[4]确定混合物中不同类别的组分在NIC和烟草成分混合物之间的相互作用中的相对重要性，以支持自我给药行为。

Research on the addictive properties of cigarettes has, for many years, focused on nicotine (NIC); studies on human subjects and experimental animals have provided compelling evidence that NIC contributes to smoking. However, it is now clear that other chemicals among the more than 4000 compounds of cigarette smoke also contribute to the addictive properties of cigarettes, at least partly by interacting with the effects of NIC on the brain. Of the many compounds present in cigarette smoke, less than a dozen of these have been identified that interact in significant ways with NIC. These compounds can be viewed as fitting into four major classes: a group of so-called minor alkaloids (e.g., anabasine, nornicotine), the p-carbolines Harman and norharman, acetaldehyde, and additional compounds that inhibit monoamine oxidase (MAO). The goal of this project is to explore, in a well characterized rat model of NIC self-administration, the reinforcing effects of NIC within the context of other components of cigarette smoke that likely contribute to its abuse liability. There are four Specific Aims: [1] To determine the effects of a cocktail of tobacco constituents on the doseresponse relationship for NIC self-administration. Hypothesis: a cocktail of tobacco constituents including the minor alkaloids, p-carbolines, acetaldehyde, and MAO inhibitors will shift the dose-response curve for NIC self-administration, such that NIC is more potent and effective in supporting self-administration. [2] To determine whether changing the concentration of the components of the cocktail of tobacco constituents will alter the acquisition and maintenance of NIC self-administration. Hypothesis: increasing the concentrations of the compounds in a cocktail of tobacco constituents will increase self-administration of a specific dose of IC whereas decreasing the concentrations will decrease self-administration. [3] To determine whether changing the concentrations of compounds in the cocktail of tobacco constituents can offset or promote the reduction in NIC self-administration caused by reducing the dose of NIC over time. Hypothesis: the reduction in NIC self-administration caused by reducing the dose of NIC can be enhanced by also reducing the concentration of the cocktail constituents whereas the effects of reducing the dose of NIC can be lessened (or even prevented) by increasing the concentration of these compounds. [4] To determine the relative importance of the different classes of components in the cocktail in the interactions between NIC and the cocktail of tobacco constituents in supporting self-administration behavior.