PDF(Pubmed)
Abstract：
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 reinforcement2,3 (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.
摘要：
芬太尼是一种强大的止痛药，可引起欣快感和积极增强1。芬太尼也会导致依赖性，由厌恶性戒断综合征定义，这助长了负增强2,3(也就是说，个人重新服用药物以避免戒断)。正负强化维持阿片类药物的消耗，导致四分之一的用户上瘾，所有成瘾药物的最大比例4。在阿片受体中，μ-阿片受体具有关键作用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，我们向小鼠注射芬太尼以急性抑制腹侧被盖区（VTA）中表达γ-氨基丁酸的神经元，导致多巴胺神经元的抑制，最终增加伏隔核中的多巴胺。VTA中µ阿片受体的敲除消除了多巴胺瞬变和正增强，但退出保持不变。我们确定了在中央杏仁核（CeA）中表达µ阿片受体的神经元，其活性在戒断期间得到增强。CeA中µ阿片受体的敲除消除了厌恶症状，这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对表达μ阿片受体的CeA神经元的光遗传学刺激。我们的研究分析了在VTA和CeA中触发正增强和负增强的神经元群体，分别。我们安排了电路组织，以开发减少芬太尼成瘾和促进康复的干预措施。
