Altering nicotine reward through conditioning

描述（由申请人提供）：包括联想学习过程在内的药物滥用的理论和实证方法在我们对药物依赖的理解和治疗方面取得了重要进展。这些方法通常将药物作为非条件刺激（US）。也就是说，药物的生物效应（如奖励、精神运动刺激）与与这些效应可靠地同时发生的刺激（如随身物品、情境线索）形成关联。最近的研究表明，一种药物的药理学（内感受性）作用也可以作为其他有益的神经递质。这种药物状态下的食欲调节史可能会加速从实验到依赖的轨迹，或者增加成瘾的持久性。本应用程序中提出的实验将使用尼古丁作为CS功能的临床前动物模型来测试这一观点的重要预测。这项研究建立在我们过去对尼古丁的研究基础上。更具体地说，大鼠将接受静脉注射（IV）尼古丁，同时短暂地接触蔗糖溶液（即食欲剂）。在初步研究中，尼古丁CS可引起食欲性CR（预期性蔗糖寻求行为）。我们的工作假设将这种CR归因于内感受性尼古丁CS通过与食欲结果可靠地配对而获得额外的食欲特性。这一假设与大多数巴甫洛夫条件反射理论一致，并表明尼古丁作为奖励的能力可能会受到食欲条件反射历史的影响。因此，本应用程序的主要目标是通过广泛使用的药物奖励-场所条件作用的临床前模型程序化地测试这一预测。以下目标将用于实现这一目标。具体目标1将确定条件反应如何随静脉尼古丁剂量（例如，0.005至0.06 mg/kg）作为CS而变化。在此过程中，我们将确定具有内感受性刺激特性的尼古丁剂量，这些尼古丁剂量也从这一学习历史中获得了额外的食欲特性。目的2将确定具有这种食欲条件反射史是否会改变尼古丁在静脉尼古丁场所条件反射任务中作为奖励（即US）的能力。我们期望尼古丁的食欲学习史可以增强其后来的奖励效应。公共卫生相关性：烟草使用反映了尼古丁成瘾导致的主要健康问题。据估计，每年造成的经济损失约为1670亿美元，尼古丁成瘾与心脏病和多种癌症的显著增加有关；非烟草使用者的健康也受到二手烟的负面影响。更好地了解烟草依赖的病因所带来的潜在好处是巨大的，这也是我们研究项目的长期目标是阐明导致尼古丁依赖的潜在联想学习过程的原因。

DESCRIPTION (provided by applicant): Theoretical and empirical approaches to drug abuse that include associative learning processes have lead to important advances in our understanding and treatment of drug dependence. These approaches typically treat the drug as an unconditioned stimulus (US). That is, the biological effects of the drug (e.g., reward, psychomotor stimulation) enter into an association with stimuli that reliably co-occur with these effects (e.g., paraphernalia, situational cues). Recent research has shown that the pharmacological (interoceptive) effects of a drug also serve as a CS for other rewarding USs. Such an appetitive conditioning history with a drug state could speed the trajectory from experimentation to dependence or increase the tenacity of the addiction. The experiments proposed in this application will test an important prediction of this perspective using a preclinical animal model in which nicotine functions as the CS. This research builds programmatically on our past research with nicotine. More specifically, rats will receive intravenous (IV) nicotine paired with brief access to a sucrose solution (i.e., an appetitive US). In preliminary research, the nicotine CS comes to evoke an appetitive CR (anticipatory sucrose-seeking behavior). Our working hypothesis attributes this CR to the interoceptive nicotine CS acquiring additional appetitive properties by virtue of being reliably paired with an appetitive outcome. This hypothesis is consistent with most Pavlovian conditioning theories and suggests that nicotine's ability to serve as a reward may be modified by an appetitive conditioning history. Accordingly, the main goal of this application is to programmatically test this prediction with a widely used preclinical model of drug reward-place conditioning. The following Aims will be used to accomplish this goal. Specific Aim 1 will determine how conditioned responding varies as a function of IV nicotine dose (e.g., 0.005 to 0.06 mg/kg) used as the CS. In doing so, we will identify nicotine doses that have interoceptive stimulus properties that also acquired additional appetitive properties from this learning history. Aim 2 will determine whether having this appetitive conditioning history will alter nicotine's ability to then function as a reward (i.e., US) in an IV nicotine place conditioning task. We expect an appetitive learning history with nicotine to potentiate its later rewarding effects. PUBLIC HEALTH RELEVANCE: Tobacco use reflects a major health problem that results from an addiction to nicotine. With an estimated annual economic cost around $167 billion, this nicotine addiction is associated with a significant increase in heart disease and many forms of cancer; the health of non-tobacco users is also negatively affected by second-hand smoke. The potential benefits that would come from a better understanding of the etiology of tobacco dependence are enormous and is the reason the long-term goal of our research program is to elucidate potential associative learning processes contributing to nicotine dependence.