Nicotine dependence: neuropharmacology in monkeys

描述（由申请人提供）：吸烟是癌症以及心血管和呼吸系统疾病的主要原因，也是美国主要的可预防死亡原因。许多因素都会导致吸烟，包括尼古丁、烟草烟雾中的其他化学物质和条件强化剂。R01提案的这一竞争性延续侧重于尼古丁和烟碱乙酰胆碱受体（nAChR）作为吸烟行为和戒烟药物治疗的关键决定因素。将使用恒河猴中的药物辨别试验来检查药物史（尼古丁治疗）对低效和高效nAChR激动剂和变构nAChR调节剂的影响。在前一个资助期，尽管伐尼克兰替代了急性给药的尼古丁的区别性刺激作用，但伐尼克兰在与临床环境相关的条件下不再能够替代尼古丁（即，慢性尼古丁治疗）。目的1检查nAChR功效（内在活性）作为nAChR激动剂模拟尼古丁的辨别刺激效应的能力的关键决定因素。将检查疗效高于伐尼克兰的新型nAChR激动剂在慢性治疗期间模拟尼古丁作用的能力，而将检查疗效低于伐尼克兰的新型nAChR激动剂在慢性尼古丁治疗期间拮抗尼古丁作用的能力。在上一个资助期进行的第二个实验中，双重正变构nAChR调节剂和竞争性可逆AChE抑制剂加兰他敏完全取代了尼古丁在恒河猴中的辨别刺激作用。目的2比较了nAChR的正构和变构配体的作用，特别是研究了变构nAChR调节剂修饰尼古丁作用的潜力。将在急性和慢性尼古丁治疗条件下检测对nAChR亚型具有选择性的阳性和阴性变构nAChR调节剂。虽然目前可用的戒烟药物在某些方面是有效的，但仍有相当大的改进余地。这些临床前研究将有助于确定药理学维度和新的方向，从而开发新的药物，进一步减少吸烟的破坏性后果。

DESCRIPTION (provided by applicant): Cigarette smoking is a leading cause of cancer as well as cardiovascular and respiratory disease and is the leading preventable cause of death in the United States. Many factors contribute to cigarette smoking, including nicotine, other chemicals in tobacco smoke, and conditioned reinforcers. This competing continuation of an R01 proposal focuses on nicotine and nicotinic acetylcholine receptors (nAChR) as critical determinants of smoking behavior and smoking cessation pharmacotherapy. Drug discrimination assays in rhesus monkeys will be used to examine the impact of drug history (nicotine treatment) on the effects of low and high efficacy nAChR agonists and allosteric nAChR modulators. In the previous funding period, whereas varenicline substituted for the discriminative stimulus effects of nicotine administered acutely, varenicline was no longer able to substitute for nicotine under conditions relevant to the clinical setting (i.e., chronic nicotin treatment). Aim 1 examines nAChR efficacy (intrinsic activity) as the critical determinant of the ability of nAChR agonists to mimic the discriminative stimulus effects of nicotine. Novel nAChR agonists with higher efficacy than varenicline will be examined for their ability to mimic the effects of nicotine during chronic treatment, whereas novel nAChR agonists with lower efficacy than varenicline will be examined for their ability to antagonize the effects of nicotine during chronic nicotine treatment. In a second experiment conducted during the previous funding period, the dual positive allosteric nAChR modulator and competitive, reversible AChE inhibitor galantamine fully substituted for the discriminative stimulus effects of nicotine in rhesus monkeys. Aim 2 compares the effects of orthosteric and allosteric ligands at nAChR and, in particular, examines the potential of allosteric nAChR modulators to modify the effects of nicotine. Both positive and negative allosteric nAChR modulators with selectivity for subtypes of nAChR will be tested under acute and chronic nicotine treatment conditions. Although currently available pharmacotherapies for smoking cessation are effective in some, there is considerable margin for improvement. These pre-clinical studies will help identify pharmacologic dimensions and novel directions upon which to develop novel medications that could further reduce the devastating consequences of cigarette smoking.