Sharp Burt M, Chen Hao
Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
Department of Pharmacology, Addiction Science, and Toxicology, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
bioRxiv. 2025 May 12:2025.05.07.652717. doi: 10.1101/2025.05.07.652717.
Individual vulnerability to opioid intake escalation is a critical but poorly understood aspect of addiction. Using genetically diverse inbred rat strains, we investigated operant oral oxycodone self-administration, identifying 'Augmenter' phenotypes that dramatically increased consumption during extended (16h vs. 4h) access-a vulnerability not predicted by standard motivation tests. A key innovation was applying lick microstructure analysis (LMA) to operationally distinguish 'consumption' from 'seeking' lick clusters within the inter-reward interval. During extended access, Augmenters of both sexes exhibited a striking surge in the of both consumption and seeking clusters (p<0.0001), driving their escalated intake. Notably, female Augmenters also showed larger seeking cluster sizes (p=0.006), suggesting enhanced reward value specifically linked to seeking behavior. In contrast, interlick interval (a palatability measure) did not differentiate phenotypes. This LMA-based approach reveals that an increased drive to seek out additional oxycodone, rather than altered hedonic impact alone, underlies the augmentation of opioid intake, offering a nuanced rodent model of heightened vulnerability and a powerful tool to dissect reward dynamics.
个体对阿片类药物摄入量增加的易感性是成瘾的一个关键但却知之甚少的方面。利用基因多样化的近交系大鼠品系，我们研究了操作性口服羟考酮自我给药行为，识别出了“增强者”表型，这些表型在延长（16小时与4小时）给药期间显著增加了药物摄入量——这是标准动机测试无法预测的一种易感性。一项关键创新是应用舔舐微观结构分析（LMA）来在奖励间隔期间从操作上区分“消费”舔舐簇和“寻求”舔舐簇。在延长给药期间，两性的“增强者”在消费舔舐簇和寻求舔舐簇方面均出现了显著激增（p<0.0001），推动了他们摄入量的增加。值得注意的是，雌性“增强者”的寻求舔舐簇尺寸也更大（p=0.006），表明与寻求行为特别相关的奖励价值增强。相比之下，舔舐间隔（一种适口性指标）并未区分不同表型。这种基于LMA的方法表明，寻求额外羟考酮的驱动力增加而非仅仅享乐影响的改变，是阿片类药物摄入量增加的基础，提供了一个关于易感性增强的细致啮齿动物模型以及一个剖析奖励动态的有力工具。
