Lehmann Collin M, Miller Nora E, Nair Varun S, Costa Kauê M, Schoenbaum Geoffrey, Moussawi Khaled
Department of Psychiatry, University of Pittsburgh, Pittsburgh, 15219, USA.
Department of Psychology, University of Alabama at Birmingham, Birmingham, 35233, USA.
Nat Commun. 2025 Jan 2;16(1):321. doi: 10.1038/s41467-024-55504-3.
Cue reactivity is the maladaptive neurobiological and behavioral response upon exposure to drug cues and is a major driver of relapse. A widely accepted assumption is that drugs of abuse result in disparate dopamine responses to cues that predict drug vs. natural rewards. The leading hypothesis is that drug-induced dopamine release represents a persistently positive reward prediction error that causes runaway enhancement of dopamine responses to drug cues, leading to their pathological overvaluation. However, this hypothesis has not been directly tested. Here, we develop Pavlovian and operant procedures in male rats to measure firing responses within the same dopamine neurons to drug versus natural reward cues, which we find to be similarly enhanced compared to cues predicting natural rewards in drug-naive controls. This enhancement is associated with increased behavioral reactivity to the drug cue, suggesting that dopamine neuronal activity may still be relevant to cue reactivity, albeit not as previously hypothesized. These results challenge the prevailing hypothesis of cue reactivity, warranting revised models of dopaminergic function in opioid addiction, and provide insights into the neurobiology of cue reactivity with potential implications for relapse prevention.
线索反应性是指个体在接触药物线索时产生的适应不良的神经生物学和行为反应，是复发的主要驱动因素。一个被广泛接受的假设是，滥用药物会导致对预测药物奖励与自然奖励的线索产生不同的多巴胺反应。主要假说是，药物诱导的多巴胺释放代表了一种持续的正向奖励预测误差，这种误差会导致对药物线索的多巴胺反应失控增强，从而导致对其病理性的高估。然而，这一假说尚未得到直接验证。在此，我们在雄性大鼠中开发了巴甫洛夫式和操作性程序，以测量同一多巴胺神经元对药物奖励线索与自然奖励线索的放电反应，我们发现与未接触过药物的对照组中预测自然奖励的线索相比，这两种线索的反应增强程度相似。这种增强与对药物线索的行为反应性增加有关，表明多巴胺神经元活动可能仍然与线索反应性相关，尽管并非如先前假设的那样。这些结果挑战了关于线索反应性的主流假说，需要对阿片类药物成瘾中多巴胺能功能的模型进行修订，并为线索反应性的神经生物学提供了见解，对预防复发具有潜在意义。
