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理论和经验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视为无条件刺激（US）。也就是说，药物的生物学效应（例如，奖励，精神刺激）与可靠地与这些效应共同发生的刺激（例如，用具、情境线索）。最近的研究表明，药物的药理学（内感受性）作用也可以作为其他有益US的CS。这样一个具有药物状态的食欲调节史可能会加速从实验到依赖的轨迹，或者增加成瘾的顽固性。本申请中提出的实验将使用临床前动物模型（其中尼古丁起CS的作用）来测试这一观点的重要预测。这项研究以我们过去对尼古丁的研究为基础。更具体地，大鼠将接受静脉内（IV）尼古丁，同时短暂接触蔗糖溶液（即，美国的胃口）。在初步研究中，尼古丁CS会引起食欲CR（预期蔗糖寻求行为）。我们的工作假设将该CR归因于内感受性尼古丁CS由于与食欲结果可靠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相一致，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，本申请的主要目标是用广泛使用的药物奖励-位置调节的临床前模型以编程方式测试该预测。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作为IV尼古丁剂量的函数而变化（例如，0.005至0.06 mg/kg）用作CS。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，这些特性也从这种学习历史中获得了额外的食欲特性。目标2将确定这种食欲调节史是否会改变尼古丁作为奖励的能力（即，美国）在一个IV尼古丁的地方条件反射任务。我们希望尼古丁的食欲学习史能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一个主要健康问题。据估计，每年的经济成本约为1670亿美元，这种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学将带来巨大的潜在益处，这也是我们研究计划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.