Systems neuropharmacology of nicotine in aversive learning in humans

尼古丁在人类厌恶学习中的系统神经药理学

• 批准号: 410802159
• 负责人: Dr. Jan Haaker
• 金额: --
• 依托单位: Institut für Systemische Neurowissenschaften
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410802159?language=en
• 关键词: Systems; neuropharmacology; nicotine; aversive; learning

The nicotinic acetylcholine transmitter system regulates aversive learning and memory in animals. Nicotine thereby enhances the coding of aversive experiences in the hippocampus and renders the resulting threat memory persistent. Additionally, nicotine impairs the inhibition of fear, which promotes that fear responses re-occur. Yet, it is unclear if these findings in rodents can be translated into neuropharmacological mechanisms in humans. To date, it has not been studied how nicotine regulates aversive learning and memory in humans.The current project aims to fill this translational gap by delineating how nicotine affects the neural systems that underlie the acquisition and inhibition of aversive learning in humans. To this end, this project employs a placebo-controlled double blind randomized design within a pharmacological fear conditioning model to test the effect of nicotine in two separate studies. First, the acute effect of nicotine on the neural systems involved in fear acquisition and extinction is tested (study 1). In a second step, the impact of chronic nicotine exposure (over four days) on the neural networks mediating extinction learning is tested (study 2). All studies employ a robust and previously established combined cue and contextual conditioning protocol, examining multiple units of analysis, such as neural responses (functional magnetic resonance imaging, fMRI), psychophysiological responses (skin-conductance), as well as subjective ratings.Originating from cellular and behavioral data in animals, the central hypothesis of this project is that acute nicotine enhances aversive learning during fear acquisition. It is moreover expected that nicotine impairs the inhibition of learned fear responses during extinction, in particular after chronic nicotine exposure. These nicotinic effects on aversive learning are expected to involve a hippocampal-centred network, connected to medial prefrontal regions and the amygdala. The anticipated results might thereby delineate how nicotine affects aversive learning in humans and establish the underlying neural basis. The proposed pharmacological challenges on fear and anxiety responses allow for delineation of acute effects of nicotine, as well as adaptions induced by chronic nicotine exposure. Moreover, these results, derived within a translational framework, allow to bridge neuropharmacological findings from animals to humans. These insights might help to understand the neurobiological etiology of anxiety related disorders as well as enable future developments of new pharmacological treatment strategies. As such, this project could mark the starting point to understand how nicotine consumption contributes as a risk factor to the currently high prevalence of anxiety related disorders and inefficient treatment.

烟碱型乙酰胆碱递质系统调节动物的厌恶学习和记忆。尼古丁因此增强了海马体中厌恶体验的编码，并使由此产生的威胁记忆持久。此外，尼古丁削弱了对恐惧的抑制，从而促进了恐惧反应的再次发生。然而，目前还不清楚这些在啮齿动物身上的发现是否可以转化为人类的神经药理学机制。到目前为止，还没有研究尼古丁如何调节人类的厌恶学习和记忆。目前的项目旨在通过描绘尼古丁如何影响人类厌恶学习的获得和抑制的神经系统来填补这一翻译空白。为此，该项目采用了安慰剂对照的双盲随机设计，在药物恐惧条件作用模型中，在两个独立的研究中测试尼古丁的效果。首先，测试尼古丁对参与恐惧获得和消除的神经系统的急性影响(研究1)。在第二步，测试长期尼古丁暴露(超过四天)对调节消退学习的神经网络的影响(研究2)。所有的研究都采用了强有力的和先前建立的线索和情境条件作用相结合的方案，考察了多个分析单元，如神经反应(功能磁共振成像)、心理生理反应(皮肤电导)以及主观评级。该项目的中心假设来自动物的细胞和行为数据，该项目的中心假设是，急性尼古丁在恐惧获得过程中增强厌恶学习。此外，人们还预计，尼古丁会在物种灭绝过程中削弱对习得恐惧反应的抑制，特别是在长期接触尼古丁之后。这些尼古丁对厌恶学习的影响预计将涉及以海马体为中心的网络，该网络连接到内侧前额叶区域和杏仁核。因此，预期的结果可能会描绘出尼古丁如何影响人类的厌恶学习，并建立潜在的神经基础。拟议的对恐惧和焦虑反应的药理学挑战允许描绘尼古丁的急性影响，以及慢性尼古丁暴露诱导的适应。此外，在翻译框架内得出的这些结果，允许从动物到人类的神经药理学发现之间的桥梁。这些见解可能有助于了解焦虑相关障碍的神经生物学病因，并使未来能够开发新的药物治疗策略。因此，这个项目可以标志着一个起点，以了解尼古丁消费如何作为一个风险因素，导致目前焦虑症的高患病率和治疗效率低下。