Nicotine dependence: neuropharmacology in monkeys

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。本R01提案关注尼古丁在介导尼古丁滥用和依赖责任中的关键作用，并关注尼古丁受体机制介导当前处方戒烟药物的行为影响，包括尼古丁（贴片和口香糖），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）。药物鉴别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。研究人员将开发一种新的药物鉴别程序，以确定尼古丁戒断反应的指标，并对该程序作为药物有效性指标的临床前效用进行评估。Aim 1验证了相同的含有尼古丁受体22的假设，特别是1422受体，介导尼古丁、伐尼克兰和胱氨酸的作用，与尼古丁拮抗剂（DH2E）的类似拮抗作用证明了这一点。目的2验证了伐尼克兰和胱氨酸在体内的激动剂效力低于尼古丁的假设。对Aim 2假设的实验支持将包括尼古丁治疗的猴子对伐尼克兰和胱氨酸的敏感性丧失（交叉耐受）大于对尼古丁的耐受性，伐尼克兰和胱氨酸无法替代相对大剂量的尼古丁，以及在尼古丁依赖的猴子中，伐尼克兰和胱氨酸替代尼古丁拮抗剂的鉴别刺激作用。目的3验证了鉴别刺激效应对尼古丁戒断反应比直接观察到的症状更敏感的假设。与戒断症状相比，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治疗是有效的，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层面，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：吸烟是导致癌症和心血管疾病的主要原因，也是导致成年人死亡的主要可预防原因（每年10%）。这笔拨款调查了目前批准的戒烟药物的受体药理学，可能会导致更好的治疗，从而减少烟草使用对健康的破坏性后果。

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.