Jehl Joachim, Ciscato Maria, Vicq Eléonore, Guyon Nicolas, Dejean de la Batie Gabrielle, Mondoloni Sarah, Frangieh Jacinthe, Mohayyaei Monir, Nguyen Claire, Pons Stéphanie, Maskos Uwe, Hardelin Jean-Pierre, Marti Fabio, Corringer Pierre-Jean, Faure Philippe, Mourot Alexandre
Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, 75005 Paris, France; Sorbonne Université, Inserm, CNRS, Neuroscience Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), 75005 Paris, France.
Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, 75005 Paris, France.
Neuron. 2025 Jun 18;113(12):1898-1907.e6. doi: 10.1016/j.neuron.2025.03.035. Epub 2025 Apr 21.
Nicotine stimulates ventral tegmental area (VTA) dopaminergic neurons, producing a rewarding effect that drives tobacco consumption. The interpeduncular nucleus (IPN) is thought to become engaged at high nicotine doses to limit drug intake, but its response dynamics are unknown. We developed a chemogenetic approach using a "suicide" antagonist that selectively attaches to designer β4 nicotinic acetylcholine receptors (nAChRs) in genetically modified mice, enabling sustained and pharmacologically specific antagonism. Local infusion in the IPN revealed that nicotine, even at low doses, simultaneously activates and inhibits two distinct populations of IPN neurons, with β4-containing nAChRs mediating only the activation response. Blocking nicotine-induced IPN activation enhanced VTA responses and increased the drug's rewarding effect in a conditioned place preference paradigm. Moreover, optogenetic inhibition of IPN projections to the laterodorsal tegmental nucleus (LDTg) replicated these behavioral effects. Our findings indicate that the IPN acts as a regulatory brake on the nicotine reward circuit via the LDTg.
尼古丁刺激腹侧被盖区（VTA）的多巴胺能神经元，产生一种驱动烟草消费的奖赏效应。人们认为，在高剂量尼古丁作用下，脚间核（IPN）会参与其中以限制药物摄入，但其反应动态尚不清楚。我们开发了一种化学遗传学方法，使用一种“自杀性”拮抗剂，该拮抗剂能选择性地附着于基因改造小鼠中的定制β4烟碱型乙酰胆碱受体（nAChRs），从而实现持续且具有药理学特异性的拮抗作用。在脚间核进行局部注射显示，即使是低剂量的尼古丁，也会同时激活和抑制脚间核中两个不同的神经元群体，其中含β4的烟碱型乙酰胆碱受体仅介导激活反应。在条件性位置偏爱范式中，阻断尼古丁诱导的脚间核激活会增强腹侧被盖区的反应，并增加药物的奖赏效应。此外，对脚间核投射到外侧背侧被盖核（LDTg）的光遗传学抑制也重现了这些行为效应。我们的研究结果表明，脚间核通过外侧背侧被盖核，对尼古丁奖赏回路起到调节制动作用。
