Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement

Article Article scientifique Article Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement eng 2024-05-22 2024-06 author Chaudun Fabrice 0000-0001-6729-7812 Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 885671 SYNAPSY Centre de recherche translationnelle en neurosciences psychiatriques (CTNP) (SYNAPM) author Python Laurena Saori Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 859568 Département de neurosciences fondamentales (NEUFO) author Liu Yu 0000-0002-9607-4228 Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 956430 Département de neurosciences fondamentales (NEUFO) author Hiver Agnès Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 798350 Département de neurosciences fondamentales (NEUFO) author Cand Jennifer Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 682652 Département de neurosciences fondamentales (NEUFO) author Kieffer Brigitte L 0000-0002-8809-8334 INSERM U1114, University of Strasbourg Institute for Advanced Study, Strasbourg, France. author Valjent Emmanuel 0000-0002-1034-606X IGF, Université de Montpellier CNRS, Inserm, Montpellier, France. author Luescher Christian 0000-0001-7917-4596 Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, Geneva, Switzerland. christian.luscher@unige.ch.,Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, Geneva, Switzerland. christian.luscher@unige.ch. 132337 Département de neurosciences fondamentales (NEUFO) 141-148 10.1038/s41586-024-07440-x 38778097 0028-0836 PMC11153127 https://www.nature.com/articles/s41586-024-07440-x 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. Animals Female Male Mice Analgesics, Opioid / pharmacology Analgesics, Opioid / administration & dosage Central Amygdaloid Nucleus / cytology Central Amygdaloid Nucleus / drug effects Central Amygdaloid Nucleus / metabolism Dopamine / metabolism Dopaminergic Neurons / drug effects Dopaminergic Neurons / metabolism Fentanyl / pharmacology Mice, Inbred C57BL Nucleus Accumbens / cytology Nucleus Accumbens / drug effects Nucleus Accumbens / metabolism Opioid-Related Disorders / metabolism Opioid-Related Disorders / pathology Optogenetics Receptors, Opioid, mu / metabolism Reinforcement, Psychology Substance Withdrawal Syndrome / metabolism Substance Withdrawal Syndrome / pathology Ventral Tegmental Area / cytology Ventral Tegmental Area / drug effects Ventral Tegmental Area / metabolism Dewey 616.8 Swiss National Science Foundation Pharmacological determinants of addiction liability 219470 CH Projects 53 Département de neurosciences fondamentales 21A 61 Département des neurosciences cliniques 226 false 271 Mécanismes cellulaires de la dépendance et de l'addiction 520 https://zenodo.org/records/10890957 Nature 630 8015 e79e3b02-bcda-4984-a59f-f2408525f149 Article (Published version) Public Article_scientifique_from_europePmc.pdf 10456214 application/pdf CC BY-4.0 75982b3e82f2552952f9600071c010c8fc975274cce4edf297d1e94724636216 01dacc2c-2248-4892-bb0f-db0d140b652e Supplemental data Public 41586_2024_7440_MOESM2_ESM.xlsx 32030 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet a39da027735fce41415bb34b8c7077e18bcafa0ee995ef80d8a5ab4ebfaeb13b openAccess Faculté de médecine / Section de médecine fondamentale / Département de neurosciences fondamentales Faculté de médecine / Section de médecine clinique / Département des neurosciences cliniques

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Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement	Nature	2024	51	186
Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice	Neuropsychopharmacology	2020	288	120

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