Distinct μ-opioid ensembles trigger positive and negative fentanyl reinforcement

• 成果类型: Article
• 署名作者: Chaudun, Fabrice; Python, Laurena; Liu, Yu; Hiver, Agnes; Cand, Jennifer; Kieffer, Brigitte L.; Valjent, Emmanuel; Luescher, Christian
• 署名单位: University of Geneva; Universite de Lorraine; Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Universite de Montpellier; Institut National de la Sante et de la Recherche Medicale (Inserm); University of Geneva
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3715
• DOI: 10.1038/s41586-024-07440-x
• 发表日期: 2024-06-06
• 页码: 141-+
• 关键词: central amygdala; nucleus-accumbens; opiate; reward; receptor; neurons; drugs; INFORMATION; mechanisms; ABUSE

摘要

Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement(1). 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 drugs(4). Among the opioid receptors, mu-opioid receptors have a key role(5), yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit gamma-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 mu-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing mu-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of mu-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 mu-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.