Effects of nicotine on dependence-related associative learning processes

描述（由申请人提供）：吸烟是美国和全世界最常见的两种可预防的死亡原因之一，并给社会带来巨大的成本。依赖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。非药物因素，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，比任何其他药物滥用都重要。尼古丁对突触可塑性和联想学习的直接影响可能促进吸烟相关刺激的条件反射，并导致对行为更强、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。提出的研究的主要原因是尼古丁促进刺激-刺激（S-S）和刺激-反应（S-R）关联的偶然形成，并增强它们对情境适应性调节的抵抗力。这种机制可能促使人们转向一种主要由条件提示控制的尼古丁寻求自动模式。在3个测试阶段中，34名健康的非吸烟者执行计算机化任务，其中偶然的S-S和S-R关联损害了灵活的任务适应表现。在前2个疗程中，中间安排2天，尼古丁（7毫克/24小时）或安慰剂贴片将按反平衡顺序双盲施用。在这些补丁会话中，每个任务范式将采用一个独特的刺激集，假设1允许直接比较尼古丁或安慰剂存在时形成的附带关联的强度。在第二次贴片后一周的测试阶段3中，参与者分别使用两组刺激分别执行一次缩短版本的任务，以评估在尼古丁或安慰剂存在下形成的联想的持久性。这将验证假设2，即在S-S和S-R关联形成过程中尼古丁的存在会减缓它们随着时间的推移而衰减。尼古丁促进人类调节机制，从而以牺牲灵活的、环境适应的行为为代价，促进自动化的吸毒行为，这一证明将为旨在证明这种机制对依赖烟草消费的贡献的全面研究奠定基础。将尼古丁依赖作为一种药物引起的不适应联想学习障碍的广泛的、有数据支持的观点，将为开发和扩展旨在打破过度学习的刺激偶然行为和促进灵活的、情境适应性控制的行为和药物治疗方法提供强有力的科学依据。目前的建议是必要的第一步，旨在证实一种特定机制的理论，这种机制可能标志着尼古丁依赖过程，并解释尼古丁自相矛盾的高滥用潜力。与这一理论解释相一致的结果将激励研究，可能导致更有效地治疗社会上最昂贵的疾病之一。

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.