Nornicotine Enantiomers and Nicotine Self Administration

描述（由申请人提供）：已知尼古丁在烟草依赖中具有重要作用。然而，除了尼古丁之外，吸烟者还暴露于烟草生物碱形式和尼古丁生物转化产生的代谢物形式的去甲尼古丁。使用人类吸烟的动物模型，我们发现去甲尼古丁在大鼠中是自我给药的，去甲尼古丁预处理可有效减少尼古丁自我给药。此外，重复给予S（-）-去甲烟碱而非R（+）-去甲烟碱可增加自发活动。 在当前项目中，我们的总体假设是S（-）-去甲尼古丁在重复注射中选择性减少尼古丁自我给药方面比R（+）-去甲尼古丁更有效。具体目的将确定去甲尼古丁对映异构体在以下方面的能力是否不同：（1）剂量依赖性降低尼古丁自我给药，（2）剂量依赖性降低蔗糖增强反应，以及（3）降低重复注射的尼古丁自我给药或蔗糖增强反应。 将训练大鼠以稳定的速率自我给予尼古丁，然后用不同剂量的S（-）-或R（+）-去甲尼古丁进行预处理。为了确定尼古丁自我给药减少的特异性，将训练单独的大鼠组以响应蔗糖强化，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，将用S（-）-或R（+）-去甲烟碱重复预处理大鼠，并测试尼古丁自我给药或蔗糖增强反应，从而评估每种去甲烟碱对映体的作用是持久的还是短暂的。 这项临床前工作的长期目标是开发一种新型戒烟药物。

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.