Systems neuropharmacology of nicotine in aversive learning in humans

烟碱乙酰胆碱递质系统调节动物的厌恶学习和记忆。因此，尼古丁增强了海马体中对厌恶经历的编码，并使由此产生的威胁记忆持续存在。此外，尼古丁会削弱对恐惧的抑制，从而促进恐惧反应的再次发生。然而，尚不清楚这些啮齿动物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述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，本项目采用安慰剂对照双盲随机设计，在药理学恐惧调节模型中分别进行两项研究，检验尼古丁的作用。首先，尼古丁对涉及恐惧获得和消除的神经系统的急性影响进行了测试（研究1）。在第二步中，测试了慢性尼古丁暴露（超过四天）对介导灭绝学习的神经网络的影响（研究2）。所有的研究都采用一个强大的和先前建立的线索和情境条件反射的组合方案，检查多个分析单元，如神经反应（功能性磁共振成像，fMRI），心理生理反应（皮肤电导），以及主观评分。从动物的细胞和行为数据出发，本项目的中心假设是急性尼古丁增强恐惧习得过程中的厌恶学习。此外，预计尼古丁会损害在灭绝期间习得性恐惧反应的抑制，特别是在慢性尼古丁暴露后。这些尼古丁对厌恶学习的影响被认为与海马体为中心的网络有关，该网络与内侧前额叶区和杏仁核相连。预期的结果可能因此描绘尼古丁如何影响人类的厌恶学习，并建立潜在的神经基础。提出的对恐惧和焦虑反应的药理学挑战允许描述尼古丁的急性效应，以及慢性尼古丁暴露诱导的适应。此外，这些结果是在翻译框架内得出的，可以将从动物到人类的神经药理学发现联系起来。这些见解可能有助于理解焦虑相关障碍的神经生物学病因，并使新的药物治疗策略的未来发展成为可能。因此，这个项目可以标志着一个起点，以了解尼古丁消费是如何作为一个风险因素，导致目前焦虑相关疾病的高患病率和治疗效率低下。

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.