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。这份R01提案的重点是尼古丁在调节尼古丁滥用和依赖倾向方面所起的关键作用，并侧重于尼古丁受体机制，这些机制介导了目前处方的戒烟药物的行为效应，包括尼古丁(贴片和口香糖)、varenicline(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)。药物识别将用于检查尼古丁受体亚型和尼古丁受体的药理(激动剂)功效，以及它们对尼古丁受体配体行为效应的贡献。将开发一种新的药物识别程序来指示尼古丁戒断，并将评估该程序的临床前效用，作为药物疗效的指标。目的1验证含有相同22个烟碱受体的假设，特别是1422受体，介导尼古丁、瓦伦尼克林和胱氨酸的作用，与尼古丁拮抗剂(DH2 E)的拮抗作用相似。目的2在体内验证伐伦尼克林和胞二磷胆碱的激动剂效应低于尼古丁的假说。对目标2假设的实验支持将包括：在尼古丁治疗的猴子中，对varenicline和cytisine的敏感性(交叉耐受性)比对尼古丁的耐受性更大，varenicline和cytisine无法替代相对较大剂量的尼古丁，以及varenicline和cytisine替代尼古丁依赖猴子中尼古丁拮抗剂的歧视性刺激效应。目的3验证辨别性刺激效应对尼古丁戒断比直接可见信号更敏感的假设。与戒烟迹象相比，尼古丁和其他目前可用的药物疗法有望更有效地减弱尼古丁戒断的歧视性刺激效应。虽然目前可用的戒烟药物疗法是有效的，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，在此基础上开发新的药物，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，也是成年人可预防的死亡原因(每年10%)。这笔赠款调查了目前批准的戒烟药物的受体药理学，并可能导致更好的治疗，从而减少烟草使用对健康造成的破坏性后果。

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 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.