Nicotine dependence: neuropharmacology in monkeys

描述(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，也是美国最主要的可预防的死亡原因。导致吸烟的因素很多，包括尼古丁、烟草烟雾中的其他化学物质和条件增强剂。这是R01提案的竞争性延续，重点是尼古丁和烟碱型乙酰胆碱受体(NAChR)作为吸烟行为和戒烟药物治疗的关键决定因素。猕猴的药物辨别试验将被用来检查药物历史(尼古丁治疗)对低效和高效nAChR激动剂和变构nAChR调节剂效果的影响。在以前的供资期间，虽然varenicline取代了急性应用尼古丁的歧视性刺激效应，但varenicline在与临床环境相关的条件下(即慢性尼古丁治疗)不再能够取代尼古丁。目的1研究nAChR效应(内源性活性)作为nAChR激动剂模拟尼古丁区别性刺激效应能力的关键决定因素。比varenicline疗效更高的新型nAChR激动剂将被检测其在慢性尼古丁治疗中模拟尼古丁效应的能力，而效率低于varenicline的新型nAChR激动剂将被检测其在慢性尼古丁治疗中对抗尼古丁效应的能力。在前一次资助期间进行的第二个实验中，双重正变构nAChR调节剂和竞争性、可逆乙酰胆碱酯酶抑制剂加兰他明完全取代了尼古丁对恒河猴的区别刺激作用。目的2比较正构和变构配体对nAChR的影响，特别是考察变构nAChR调节剂对尼古丁影响的可能性。对nAChR亚型具有选择性的正负变构nAChR调节剂将在急性和慢性尼古丁治疗条件下进行测试。虽然目前可用的戒烟药物疗法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方面和新的方向，在此基础上开发可以进一步减少吸烟的破坏性后果的新药。

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.