Nornicotine Enantiomers and Nicotine Self Administration

描述(申请人提供)：众所周知，尼古丁在烟草依赖中起着重要作用。然而，除了尼古丁，吸烟者还会接触到去甲尼古丁，既有烟草生物碱的形式，也有尼古丁生物转化的代谢物。利用人类吸烟的动物模型，我们发现去甲尼古丁在大鼠体内是自我给药的，去甲尼古丁预处理在减少尼古丁自我给药方面是有效的。此外，反复给药S(-)-去甲烟碱，而不是R(+)-去甲烟碱，可增加运动活动。在目前的项目中，我们的总体假设是，S(-)-去甲烟碱将比R(+)-去甲尼古丁在选择性地减少重复注射尼古丁的自身给药方面更有效。具体的目标将决定去甲尼古丁对映体在以下方面的能力是否不同：(1)剂量依赖性地减少尼古丁自身给药，(2)剂量依赖性地减少蔗糖增强的反应，以及(3)减少尼古丁的自身给药或反复注射时的蔗糖增强的反应。训练大鼠以稳定的速度自我给予尼古丁，然后用不同剂量的S(-)或R(+)去甲尼古丁进行预处理。为了确定尼古丁自身给药减少的特异性，将对不同组的大鼠进行蔗糖强化反应的训练，并将用不同剂量的S(-)或R(+)-去甲尼古丁进行预处理。在另一项实验中，大鼠将反复接受S(-)或R(+)-去甲尼古丁的预处理，并测试尼古丁自我给药或蔗糖强化的反应，从而评估每种去甲尼古丁对映体的作用是长期的还是短暂的。这项临床前工作的长期目标是开发一种新的戒烟药物。

DESCRIPTION (provided by applicant): Nicotine is known to have an important role in tobacco dependence. However, in addition to nicotine, smokers are exposed to nornicotine both in the form of a tobacco alkaloid and as a metabolite that results from biotransformation of nicotine. Using an animal model of tobacco smoking in humans, we have found that nornicotine is self-administered in rats and that nornicotine pretreatment is effective in reducing nicotine self-administration. In addition, repeated administration of S(-)-nornicotine, but not R(+)-nornicotine, increases locomotor activity. In the current project, our overall hypothesis is that S(-)-nornicotine will be more potent than R(+)-nornicotine in selectively decreasing nicotine self-administration across repeated injections. The specific aims will determine if the nornicotine enantiomers differ in their ability to (1) dose dependently decrease nicotine self-administration, (2) dose-dependently decrease sucrose-reinforced responding, and (3) decrease nicotine self-administration or sucrose-reinforced responding across repeated injections. Rats will be trained to self-administer nicotine to a stable rate and then will be pretreated with varying doses of either S(-)- or R(+)-nornicotine. To determine the specificity of the decrease in nicotine self- administration, separate groups of rats will be trained to respond for sucrose reinforcement and will be pretreated with varying doses of either S(-)- or R(+)-nornicotine. In another experiment, rats will be pretreated repeatedly with either S(-)- or R(+)-nornicotine and tested for nicotine self-administration or sucrose-reinforced responding, thus assessing if effect of each nornicotine enantiomer is long-lasting or transient. The long-range goal of this preclinical work is to develop a novel medication for smoking cessation.