Nicotine dependence: neuropharmacology in monkeys

尼古丁依赖：猴子的神经药理学

• 批准号: 7654769
• 负责人: Lance R McMahon
• 金额: $ 33.37万
• 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/7654769
• 关键词: Address; Adult; Agonist; Attenuated; Behavioral; Behavioral Assay; Biological Assay; Bupropion; Cancer Etiology; Cardiovascular Diseases; Cardiovascular system; 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; public health relevance; 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道疾病的主要原因，是美国可预防的死亡原因。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增强剂。该R01提案的重点是尼古丁在介导尼古丁的滥用和依赖责任中所发挥的至关重要的作用，并着重于尼古丁受体机制，介导了当前处方药物在包括尼古丁（烟灰和牙龈），varenicline，varenicline（varenicacy）（varenicacy）（varenicacy）（低效率）上的行为影响的尼古丁受体机制（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）。药物歧视将用于检查尼古丁受体的尼古丁受体亚型和药理学（激动剂）功效，及其对尼古丁受体配体行为影响的贡献。将开发一种新型的药物歧视程序来指定尼古丁戒断，并将该程序作为临床前实用程序作为药物有效性的指数进行评估。 AIM 1检验了以下假设：相同的22个含22个尼古丁受体，特别是1422受体，介导了尼古丁，葡萄烯和氰胺的作用，这是与尼古丁拮抗剂（DH2E）相似的拮抗作用所证明的。 AIM 2检验了一种假设，即在体内，葡萄烯和氰基菌具有比尼古丁的激动剂疗效更低的假设。对AIM 2假设的实验支持将包括对尼古丁处理的猴子中对尼古丁的耐受性的敏感性丧失（跨耐受性），而对尼古丁的耐受性，varenicline和cytisine的失败代替了相对较大的烟碱，以及尼古丁的相对大剂量尼古丁拮抗剂在尼古丁依赖性猴子中的歧义性刺激作用的varenicline和cytisine of。 AIM 3检验了以下假设：鉴别刺激效应比直接观察的迹象更敏感尼古丁的戒断。与戒断的迹象相比，尼古丁和其他目前可用的药物治疗将更有效地减弱尼古丁戒断的歧视性刺激作用。尽管目前可用于戒烟的药物治疗效果有效，但改进的余量有相当大的余量。这些临床前研究将有助于确定开发新型药物的药理维度，从而进一步减少吸烟的毁灭性后果。公共卫生相关性：吸烟是癌症和心血管疾病的主要原因，并且是成年人的可预防原因（每年10％）。该赠款调查了当前批准的戒烟药物的受体药理学，并可能导致更好的治疗，从而减少烟草使用的毁灭性健康后果。