Nicotine dependence: neuropharmacology in monkeys

尼古丁依赖：猴子的神经药理学

• 批准号: 9581856
• 负责人: Lance R McMahon
• 金额: $ 17.07万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-11 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9581856
• 关键词: Nicotine; dependence; neuropharmacology; monkeys

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.

描述（由申请人提供）：在美国，吸烟是癌症、心血管和呼吸系统疾病的主要原因，也是可预防的主要死亡原因。许多因素导致吸烟，包括尼古丁、烟草烟雾中的其他化学物质和条件强化物。这项R01提案的竞争性延续侧重于尼古丁和尼古丁乙酰胆碱受体（nAChR）作为吸烟行为和戒烟药物治疗的关键决定因素。恒河猴的药物鉴别试验将用于检查药物史（尼古丁治疗）对低效和高效nAChR激动剂和变构nAChR调节剂效果的影响。在上一个资助期内，虽然伐尼克兰替代了尼古丁急性给予的区别性刺激效应，但在与临床环境相关的条件下（即慢性尼古丁治疗），伐尼克兰不再能够替代尼古丁。目的1检验nAChR功效（内在活性）作为nAChR激动剂模拟尼古丁的鉴别刺激效应的关键决定因素。在慢性尼古丁治疗过程中，将研究比伐尼克兰疗效更高的新型nAChR激动剂是否能模拟尼古丁的作用，而在慢性尼古丁治疗过程中，将研究比伐尼克兰疗效更低的新型nAChR激动剂是否能拮抗尼古丁的作用。在上一个资助期内进行的第二个实验中，双阳性变构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比较正构配体和变构配体对nAChR的影响，特别是研究变构nAChR调节剂对尼古丁影响的潜在影响。在急性和慢性尼古丁治疗条件下，将测试对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治疗对某些人有效，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开发新药物的新方向，从而进一步减少吸烟的破坏性后果。