Effects of nicotine on dependence-related associative learning processes

尼古丁对依赖相关联想学习过程的影响

• 批准号: 8824263
• 负责人: Britta Hahn
• 金额: $ 7.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824263
• 关键词: Accounting; Adaptive Behaviors; Animals; Association Learning; Back; Behavior; Behavior Control; Behavior Therapy; Cause of Death; Crossover Design; Cues; Data; Dependence; Disease; Double-Blind Method; Equilibrium; Future; Health; Human; Lead; Learning; Maintenance; Medical; Nicotine; Nicotine Dependence; Outcome; Participant; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Placebos; Play; Population; Prevalence; Process; Productivity; Relative (related person); Resistance; Response to stimulus physiology; Role; Schedule; Smoker; Smoking; Smoking Behavior; Societies; Stimulus; Synaptic plasticity; Task Performances; Testing; Time; Tobacco Dependence; Tobacco smoking; Tobacco use; cigarette smoking; classical conditioning; computerized; conditioning; cost; design; drug of abuse; effective therapy; flexibility; indexing; learning extinction; nicotine abuse; non-smoker; novel; public health relevance; response; success; theories; treatment strategy; years of life lost

DESCRIPTION (provided by applicant): Tobacco smoking is among the two most common preventable causes of death in the US and world- wide, and causes enormous cost to society. The continued substantial prevalence of dependent tobacco consumption and poor quit success may reflect our incomplete understanding of the nicotine dependence process. Non-pharmacological factors, such as the behavioral control exerted by internal and external drug- associated stimuli, appear to play a dominant role in nicotine dependence, more than for any other drug of abuse. Nicotine's direct effects on synaptic plasticity and associative learning may facilitate the conditioning of smoking-associated stimuli and lead to stronger, more enduring cue control over behavior. However, such theories have not been backed by direct experimental evidence in humans. of the pro- posed study is that nicotine facilitates the incidental formation o stimulus-stimulus (S-S) and stimulus- response (S-R) associations and strengthens their resistance to context-adaptive modulation. This mechanism may promote a shift towards an automatic mode of nicotine-seeking largely controlled by conditioned cues. In 3 test sessions, 34 healthy non-smokers will perform computerized tasks in which incidental S-S and S-R associations impair flexible task-adaptive performance. In the first 2 sessions, scheduled with 2 intermediate days, a nicotine (7 mg/24 hrs) or placebo patch will be administered double-blind, in a counter- balanced sequence. In each of these patch sessions, each task paradigm will employ a unique stimulus set, Hypothesis 1 allowing direct comparison of the strength of incidental associations formed in the presence of nicotine or placebo . In test session 3, scheduled one week after the second patch session, participants perform shortened versions of the tasks, once with each of the two stimulus sets, to assess the persistence of associations formed in the presence of nicotine or placebo. This will test Hypothesis 2 that the presence of nicotine during the formation of S-S and S-R associations slows their decay over time. The demonstration that nicotine promotes conditioning mechanisms in humans that could promote automatized drug-taking behavior at the expense of flexible, context-adaptive behavior would lay the groundwork for comprehensive studies aimed at demonstrating the contribution of such mechanisms to dependent tobacco consumption. A broadened, data-backed view of nicotine dependence as a disorder of drug-induced maladaptive associative learning would provide a strong scientific rationale for developing and expanding behavioral and pharmacological treatment approaches aimed at breaking over-learned stimulus-contingent behavior and promoting flexible, context-adaptive control. The present proposal constitutes the necessary first step towards substantiating theories of a specific mechanism that may mark the nicotine dependence process and explain the paradoxically high abuse potential of nicotine. Results consistent with this theoretical account would motivate studies that may lead to more effective treatments of one of the most costly disorders to society.

描述（由申请人提供）：吸烟是美国和世界范围内两种最常见的可预防死亡原因之一，并给社会造成巨大成本。依赖性烟草消费的持续大量流行和戒烟成功率低可能反映了我们对尼古丁依赖过程的不完全理解。非药理学因素，如由内部和外部药物相关刺激施加的行为控制，似乎在尼古丁依赖中起主导作用，超过任何其他药物滥用。尼古丁对突触可塑性和联想学习的直接影响可能有助于对吸烟相关刺激的调节，并导致对行为的更强，更持久的线索控制。然而，这些理论还没有得到人类直接实验证据的支持。尼古丁促进了刺激-刺激（S-S）和刺激-反应（S-R）联想的偶然形成，并增强了它们对情境适应性调节的抵抗力。这种机制可能会促进转向尼古丁寻求的自动模式，主要由条件线索控制。在3个测试阶段中，34名健康的非吸烟者将执行计算机化任务，其中偶然的S-S和S-R关联损害灵活的任务适应性表现。在前2个阶段（计划有2个中间日），尼古丁（7 mg/24小时）或安慰剂贴剂将以双盲、反平衡顺序给药。在每个补丁会话中，每个任务范式将采用独特的刺激集，假设1允许直接比较在尼古丁或安慰剂存在下形成的偶然关联的强度。在测试阶段3中，计划在第二个贴片阶段后一周，参与者执行缩短版本的任务，两个刺激组各一次，以评估在尼古丁或安慰剂存在下形成的关联的持久性。这将检验假设2，即在S-S和S-R关联形成期间尼古丁的存在减缓了它们随时间的衰减。尼古丁促进人类的条件反射机制，可以促进自动化的吸毒行为，而牺牲灵活的，适应环境的行为，这一证明将为旨在证明这种机制对依赖性烟草消费的贡献的全面研究奠定基础。尼古丁依赖是一种药物诱导的适应不良联想学习障碍，这一广泛的、有数据支持的观点将为开发和扩展行为和药理学治疗方法提供强有力的科学依据，这些方法旨在打破过度学习的刺激相关行为，促进灵活的、情境适应性控制。目前的建议构成了必要的第一步，以证实一个特定的机制，可能标志着尼古丁依赖的过程，并解释尼古丁的矛盾高滥用潜力的理论。与这一理论解释相一致的结果将激励研究，这些研究可能导致对社会代价最高的疾病之一进行更有效的治疗。