Nunes-Freitas André Luiz, Soni Neeraj, Polli Filip S, Kohlmeier Kristi A
Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark; Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil.
Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
Neurotoxicol Teratol. 2021 Sep-Oct;87:106980. doi: 10.1016/j.ntt.2021.106980. Epub 2021 Apr 8.
Using drugs of abuse while pregnant has tremendous negative consequences for the offspring, including an enhanced risk for substance use disorder (SUD). This vulnerability suggests that gestational exposure to drugs alters the developmental trajectory of neurons important in SUD processes, which could lead to later life changes in responsiveness to motivationally salient stimuli. The laterodorsal tegmentum (LDT) gates the behaviorally relevant firing pattern signaling stimuli saliency in mesoaccumbal circuits. Accordingly, any alterations in LDT functionality could alter output, and play a role in negative outcomes on motivated behavior associated with early-life nicotine exposure. Therefore, we investigated whether prenatal exposure to nicotine (PNE), which is a known teratogen, altered responsiveness of LDT neurons to alcohol by conducting electrophysiology in brain slices. Alcohol induced an outward current in control LDT cells, which was not seen in PNE LDT neurons. The frequency of mEPSCs was significantly decreased by alcohol in LDT PNE cells and accompanied by a decrease in action potential frequency, which were actions not seen in controls. Changes in baseline activity of PNE LDT cells were also observed. In summary, PNE LDT neurons showed alterations in baseline activity and membrane and synaptic responses to postnatal exposures to alcohol. The differences in PNE baseline activity and alcohol responses likely lead to differential output from the LDT to mesoaccumbal targets that could play a role in biasing coding of relevant stimuli, which could participate in the enhanced proclivity for development of SUD in those exposed during gestation to nicotine.
孕期滥用药物会对后代产生巨大的负面影响，包括增加物质使用障碍（SUD）的风险。这种易感性表明，孕期接触药物会改变SUD过程中重要神经元的发育轨迹，这可能导致日后对动机性显著刺激的反应性发生变化。外侧背盖区（LDT）控制着中脑伏隔核回路中与行为相关的放电模式，该模式可表明刺激的显著性。因此，LDT功能的任何改变都可能改变输出，并在与早年尼古丁暴露相关的动机行为的负面结果中发挥作用。因此，我们通过对脑片进行电生理研究，调查了孕期暴露于已知致畸剂尼古丁（PNE）是否会改变LDT神经元对酒精的反应性。酒精在对照LDT细胞中诱导出外向电流，而在PNE LDT神经元中未观察到这种电流。酒精显著降低了LDT PNE细胞中微小兴奋性突触后电流（mEPSCs）的频率，并伴随着动作电位频率的降低，而在对照中未观察到这些现象。我们还观察到PNE LDT细胞的基线活动发生了变化。总之，PNE LDT神经元在基线活动以及对产后酒精暴露的膜和突触反应方面表现出改变。PNE基线活动和酒精反应的差异可能导致LDT向中脑伏隔核靶标的输出不同，这可能在偏向相关刺激的编码中发挥作用，进而可能导致孕期暴露于尼古丁的个体中SUD发展倾向增强。
