Nicotine dependence: neuropharmacology in monkeys

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剂。本R01提案重点关注尼古丁在介导尼古丁滥用和依赖倾向方面发挥的关键作用，并重点关注尼古丁受体机制介导目前处方的戒烟药物的行为效应，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）。药物辨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。将开发一种新的药物鉴别程序来指示尼古丁戒断，并将评价该程序作为药物有效性指标的临床前效用。目的1检验以下假设：相同的含22个尼古丁受体，特别是1422个受体，介导尼古丁、伐尼克兰和野靛碱的作用，如与尼古丁拮抗剂（DH2E）的类似拮抗作用所证明。目的2验证伐尼克兰和金雀花碱的体内激动剂效力低于尼古丁的假设。目标2假设的实验支持将包括尼古丁处理猴对伐尼克兰和金雀花碱的敏感性损失（交叉耐受性）大于对尼古丁的耐受性，伐尼克兰和金雀花碱未能替代相对较大剂量的尼古丁，以及伐尼克兰和金雀花碱替代尼古丁依赖猴中尼古丁拮抗剂的辨别刺激效应。目的3测试的假设，歧视性刺激效果更敏感的尼古丁戒断比直接观察到的迹象。与戒断体征相比，尼古丁和其他现有药物治疗预计可更有效地减弱尼古丁戒断的辨别性刺激效应。虽然目前可用的戒烟药物是有效的，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，以开发新的药物，进一步减少吸烟的破坏性后果。

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.