Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement¹. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement^2,3 (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs⁴. Among the opioid receptors, µ-opioid receptors have a key role⁵, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.

芬太尼是一种强效止痛药，可引起欣快感和积极强化 ¹ 。芬太尼还会导致依赖性，即厌恶戒断综合症，它会加剧负强化 ^2,3 （即个体重新服用药物以避免戒断）。正强化和负强化维持阿片类药物的消耗，这导致四分之一的使用者成瘾，这是所有成瘾药物中最大的比例 ⁴ 。在阿片受体中，μ-阿片受体起着关键作用 ⁵ ，但最终导致成瘾的回路适应的诱导位点仍然未知。在这里，我们给小鼠注射芬太尼，以急性抑制腹侧被盖区（VTA）表达γ-氨基丁酸的神经元，引起多巴胺神经元的去抑制，最终增加伏隔核中的多巴胺。 VTA 中 µ-阿片受体的敲低消除了多巴胺瞬变和正强化，但戒断作用保持不变。我们在中央杏仁核（CeA）中发现了表达μ阿片受体的神经元，其活性在戒断期间增强。 CeA 中 µ-阿片受体的敲低消除了厌恶症状，表明它们介导了负强化。因此，光遗传学刺激引起位置厌恶，小鼠很容易学会按下杠杆来暂停表达μ阿片受体的 CeA 神经元的光遗传学刺激。我们的研究解析了分别触发 VTA 和 CeA 正强化和负强化的神经元群。我们布置了巡回组织，以制定减少芬太尼成瘾和促进康复的干预措施。