Nicotine dependence: neuropharmacology in monkeys

尼古丁依赖：猴子的神经药理学

• 批准号: 8215803
• 负责人: Lance R McMahon
• 金额: $ 32.09万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215803
• 关键词: Address; Adult; Agonist; Attenuated; Behavioral; Behavioral Assay; Biological Assay; Bupropion; Cancer Etiology; Cardiovascular Diseases; Catecholamines; Cause of Death; Chemicals; Chronic; Dependence; Dimensions; Dose; Effectiveness; Failure; Grant; Health; Individual; Lead; Ligands; Lung diseases; Macaca mulatta; Measures; Mediating; Monkeys; Neuropharmacology; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Procedures; Role; Site; Stimulus; Testing; Therapeutic; Tobacco smoke; Tobacco use; Training; United States; Withdrawal; Work; base; cigarette smoking; comparative efficacy; cytisine; drug discrimination; in vivo; indexing; inhibitor/antagonist; nicotine patch; novel; pre-clinical; preclinical study; receptor; reinforcer; reuptake; smoking cessation; varenicline

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 R01 proposal focuses on the crucial role that nicotine plays in mediating the abuse and dependence liability of nicotine, and focuses on nicotine receptor mechanisms mediating the behavioral effects of currently prescribed medications for smoking cessation including nicotine (patch and gum), varenicline (low efficacy nicotine agonist), and bupropion (catecholamine reuptake inhibitor and nicotine antagonist). Drug discrimination will be used to examine nicotine receptor subtypes and pharmacologic (agonist) efficacy at nicotine receptors and their contribution to the behavioral effects of nicotine receptor ligands. A novel drug discrimination procedure will be developed to index nicotine withdrawal and the procedure will be evaluated for its pre-clinical utility as an index of medication effectiveness. Aim 1 tests the hypothesis that the same 22-containing nicotine receptors, specifically 1422 receptors, mediate the effects of nicotine, varenicline, and cytisine, as evidenced by similar antagonism with nicotine antagonists (DH2E). Aim 2 tests the hypothesis that varenicline and cytisine have lower agonist efficacy than nicotine in vivo. Experimental support for the hypothesis of Aim 2 will include greater loss of sensitivity (cross-tolerance) to varenicline and cytisine than tolerance to nicotine in nicotine-treated monkeys, failure of varenicline and cytisine to substitute for a relatively large dose of nicotine, and substitution of varenicline and cytisine for the discriminative stimulus effects of a nicotine antagonist in nicotine-dependent monkeys. Aim 3 tests the hypothesis that discriminative stimulus effects are more sensitive to nicotine withdrawal than directly observable signs. Nicotine and other currently available pharmacotherapies are expected to attenuate more effectively the discriminative stimulus effects of nicotine withdrawal as compared to signs of withdrawal. Although currently available pharmacotherapies for smoking cessation are effective, there is considerable margin for improvement. These pre-clinical studies will help identify pharmacologic dimensions upon which to develop novel medications that could further reduce the devastating consequences of cigarette smoking. PUBLIC HEALTH RELEVANCE: Cigarette smoking is a leading cause of cancer and cardiovascular disease and is the leading preventable cause of death in adults (10% annually). This grant investigates the receptor pharmacology of currently approved medications for smoking cessation and could lead to better treatment, thereby decreasing the devastating health consequence of tobacco use.

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物。该 R01 提案重点关注尼古丁在调节尼古丁滥用和依赖倾向中所起的关键作用，并重点关注尼古丁受体机制介导目前处方戒烟药物的行为影响，包括尼古丁（贴剂和口香糖）、伐尼克兰（低效）尼古丁激动剂）和安非他酮（儿茶酚胺再摄取抑制剂和尼古丁拮抗剂）。药物区分将用于检查尼古丁受体亚型和尼古丁受体的药理学（激动剂）功效及其对尼古丁受体配体行为效应的贡献。将开发一种新的药物辨别程序来索引尼古丁戒断，并将评估该程序作为药物有效性指标的临床前效用。目标 1 测试了这样的假设：相同的 22 个尼古丁受体，特别是 1422 个受体，介导尼古丁、伐尼克兰和金雀花碱的作用，与尼古丁拮抗剂 (DH2E) 的类似拮抗作用证明了这一点。目标 2 检验了伐尼克兰和金雀花碱在体内的激动剂功效低于尼古丁的假设。对目标 2 假设的实验支持将包括，在接受尼古丁治疗的猴子中，与对尼古丁的耐受性相比，对伐尼克兰和金雀花碱的敏感性（交叉耐受性）损失更大，伐尼克兰和金雀花碱无法替代相对大剂量的尼古丁，以及替代伐尼克兰和金雀花碱对尼古丁依赖性猴子的尼古丁拮抗剂的辨别刺激作用。目标 3 检验了这样的假设：区别性刺激效应比直接观察到的迹象对尼古丁戒断反应更敏感。与戒断症状相比，尼古丁和其他目前可用的药物疗法预计将更有效地减弱尼古丁戒断的歧视性刺激作用。尽管目前可用的戒烟药物疗法是有效的，但仍有很大的改进空间。这些临床前研究将有助于确定药理学维度，据此开发新药物，进一步减少吸烟的破坏性后果。公共卫生相关性：吸烟是癌症和心血管疾病的主要原因，也是成年人可预防死亡的主要原因（每年 10%）。这笔赠款研究了目前批准的戒烟药物的受体药理学，可能会带来更好的治疗，从而减少烟草使用对健康造成的破坏性后果。